In a lab, an egg yolk is injected with a mysterious green fluid. In just a second, an identical copy comes out of the first yolk. Meanwhile on the Hollywood Walk of Fame, legendary celebrity Elisabeth finally gets her star.
During the first year, fans gather around the star to show their love, but as time passes people stop paying attention to it. Cracks appear yet nobody fixes them. Now that she’s middle-aged, it’s harder for Elisabeth to get job offers and she ends up as the host of an aerobics show.
One day she discovers the women’s bathroom is out of order, so she uses the men’s. While she’s inside a stall, the network’s president Harvey comes in to relieve himself without interrupting his phone call. He keeps complaining about Elisabeth’s age and how his show needs someone fresh and young.
After he leaves, Elisabeth comes out and stares at herself in the mirror as she processes what she just heard. At lunch Harvey fires Elisabeth, although he’s super vague about it because he’s only brave in private. On her way home, Elisabeth is distracted by seeing her billboard being taken down and her car is hit by an incoming vehicle, causing a serious crash.
Later at the hospital, the doctor tells her she doesn’t have a single scratch, so she can go home. When he notices the date on the profile, he wishes her a happy birthday, causing her to finally have a breakdown. After the doctor leaves, the nurse announces he must do one more exam and starts examining her spine.
He concludes she’s the “perfect candidate” before giving her jacket so she can finally go. Once outside, Elisabeth discovers the nurse left a little package in her jacket pocket. She unwraps it to find a flash drive with the words “The Substance” plus a telephone number, the paper also says “it changed my life”.
At that moment she’s approached by Fred, who used to go to school with her. He says she’s as beautiful as she was back then and gives her his number. At home, Elisabeth watches the contents of the flash drive, which is a video advertising something called “The Substance”.
It provides the user with the experience of living as a younger and better version of themselves, switching between the young and old bodies every seven days. Thinking it’s a scam, Elisabeth throws the flash drive in the trash. That night she goes to a bar and gets drunk alone.
However she quickly returns home and throws up because at her age drinking doesn’t come as easily. Feeling very frustrated, she throws a snow globe at a framed poster of her younger self. Afterward she retrieves the flash drive and calls the number.
A mysterious voice asks for her address and gives her one in return before hanging up. The next morning she is upset to find an ad for a casting call in the newspaper saying they want the next Elisabeth for their show. After throwing the newspaper away, Elisabeth checks her mail and finds a black envelope containing just a card with the number 503.
Then she goes to the address they gave her, which is located in a shady alley. She uses the card to open the door, which only goes up halfway and takes her to a very dark corridor. Eventually she reaches a room with deposit boxes, so she opens the one with her number and finds a cardboard box.
Elisabeth returns home and finally opens the box, where she finds a kit with the Substance. There’s an activator, a stabilizer, a switch, and special food. The instructions explain she must activate only once, stabilize every day, change bodies every seven days without exception, and remember she’s one.
After taking a look at her body in the bathroom, Elisabeth injects herself with the green liquid. For a few seconds nothing happens, until suddenly Elisabeth feels great pain and collapses on the floor. Her body writhes for a while as her pupils duplicate and moving bulges appear on her back.
Suddenly a giant slit opens her body and an entire human being comes out of her. Checking on the mirror, Elisabeth realizes she’s now inside a much younger body. When taking a closer look, she can see the original green eyes hiding behind her new blue.
After throwing up some of the green liquid, the new body closes up the slit in the old body and injects it with the special food packs. The following morning, the new Elisabeth hears a screeching noise and notices her nose is bleeding, which reminds her she must stabilize every day. Using the kit from the box, she takes spine fluid from the old body and injects it into the new one, which immediately stops the bleeding and gets rid of the noise.
Afterward the new body buys some nice clothes and goes to the audition, introducing herself as Sue. Harvey is very impressed by her and immediately hires her, but Sue will only accept under one condition: she can work every other week because she must take care of her sick mother. Desperate to have her beauty in his channel, Harvey agrees.
During the following week, Sue enjoys being the center of attention again and soon there’s a new billboard with her face. She makes sure to stabilize every day, although she never moves Elisabeth’s body from the bathroom floor. At the end of the week, Sue uses the change kit to connect both bodies and a blood exchange ensues.
Sue soon passes out and Elisabeth is active again, immediately feeling the pain on her back from the scar. She goes to the station and Harvey gives her a box with her things, barely saying goodbye. Her week as Elisabeth is incredibly dull and boring, and she can’t wait to be Sue again.
Every day she makes sure to stabilize the body and another black envelope arrives when the refill kit is ready for pickup, which means another visit to the shady alley. When Sue returns the next week, she looks for a hollow wall in the bathroom and starts breaking it down, intending to build a hideout for the other body. She spends several hours working and a neighbor comes to the apartment to complain about the noise, however he instantly calms down when he sees Sue.
She tells him Elisabeth moved out and closes the door on his face when he tries flirting with her. Once the secret room is ready, Sue hides Elisabeth and her big poster inside. Now Sue can start her new life for real.
She hosts her show on TV and everyone adores her thanks to her amazing body, which she doesn’t hesitate to show off. At night she goes partying with other young people and even brings a guy home to do the naughty. However their fun is interrupted when Sue starts hearing the screeching noise and her nose bleeds, announcing her time is up.
She runs to bathroom and opens the secret room to find Elisabeth’s body writhing as it finishes the last food bag. Desperate to go back to the guy, Sue breaks the rules: instead of changing bodies, she recycles a stabilizer tube and extracts more fluid from Elisabeth to inject in her body. As soon as she’s feeling better, she returns to her guest and they have a naughty night together.
When the zipper on Sue’s clothes is opened, a bunch of organs and blood come out of her body. However this is just a dream that wakes Sue in the middle of the night, and she finishes the body exchange. Elisabeth wakes up in the morning to discover the mess Sue left in the apartment and a note from the man, which says he’ll come back later for his bike.
At that moment Elisabeth is horrified to discover that the extra hours she spent as Sue have consequences and now part of her hand looks very old. She runs to wash it off but nothing happens. Then Elisabeth calls the number from the flash drive, but the mysterious voice tells her there’s no fixing this.
When Elisabeth tries to blame Sue for it, the voice reminds her that Sue isn’t a separate person. Afterward Elisabeth cleans the apartment while watching TV and gets to see Sue on the show. The beauty of the young body irritates her and she ends up turning it off.
Then the neighbor knocks on her door again and tries to ask her out, but Elisabeth never answers him. That afternoon, Elisabeth goes to the alley for her refill box and hears a noise that suspiciously sounds like the word “Sue”. Terrified, she immediately runs away with her box.
Elisabeth ends up entering a diner and keeps her bad hand hidden in a glove. Suddenly an old man says that seven days feel like a long time, and Elisabeth notices he has the same birthmark on his arm as the nurse who gave her the flash driver. He winks at her and accidentally drops his wallet, which contains a card with the number 207.
This confirms the nurse was this man’s young body created by the Substance. He starts sharing his experience: it becomes very lonely to simply be alive, and each time it gets harder to remember the old body deserves to exist and matters too. When he asks her if the young body has started eating away at her, Elisabeth runs away in fear.
Outside her apartment she bumps into the guy from last night who came for his bike. He yells at her before leaving, which is another reminder of how people perceive her in this body. Needing to feel better about herself, Elisabeth decides to call Fred and agrees to a date.
She puts on her best clothes but when it comes to make-up, she copies Sue’s style. On her way out, she sees the billboard with Sue’s picture and it makes her feel bad about her body again. Elisabeth grabs some accessories and fixes the make-up to have a style that matches her age.
However when she tries to leave again, the sight of the billboard continues to haunt her. Once again she goes to the bathroom and has a breakdown as she messes with her make-up and hair. In the end she doesn’t go to the date and ignores all the texts Fred sends her.
The following week while Sue is recording her show, she freaks out when she feels a bulge appearing on her rear. However when she checks, there’s nothing there. The team plays the recording on the big screen to check what happened and Sue feels incredibly exposed, so she puts on a robe and rushes to her dressing room.
Seeing the bulge again, she starts pushing it through her body until it gets to her stomach, then she reaches inside through her belly button to pull out the bulge which turns out to be a chicken leg. The next time she wakes up after the exchange, Sue finds the food leftovers left by Elisabeth, who has been eating a lot to deal with her depression. A furious Sue call the number to complain, explaining that she barely has any time to enjoy herself because of work while Elisabeth spends her days eating and watching TV.
The voice’s only answer is to remind her there’s no “she and you”. When she goes to work, Sue is shocked to discover that the taping for her show has been canceled and she gets very nervous when she’s called to Harvey’s office. However he has good news: she’s become so popular that they want her to host a New Year’s Eve special.
Obviously Sue accepts and goes home to take more liquid from Elisabeth’s spine, claiming she can’t miss this opportunity. Her career is going so well that Sue continues to do this for several days, causing the hole on Elisabeth’s back to get green and nasty. When Elisabeth finally comes back, she screams when she sees her body.
It’s very old and decrepit, and her legs can barely move. Elisabeth calls the number to complain about Sue again and the voice offers to cancel the experience, which means Sue wouldn’t come back. Remembering her new successful career, Elisabeth turns the offer down and keeps scolding herself for forgetting they’re the same person.
On the last night, Elisabeth tries to get up from her chair but her leg won’t cooperate so she has to move it manually, which causes her a lot of pain. She grabs a recipe book and starts cooking great amounts of food while listening to Sue being interviewed on TV. Sue mocks the old show and Elisabeth, who furiously begins throwing food at the screen.
She feels like the billboard is mocking her too, so she throws eggs at the window and covers it with newspaper. Before making the change, Elisabeth yells at herself in the mirror, trying to remind Sue to control herself. When Sue wakes up, she finds the apartment in a disgusting state and starts insulting Elisabeth.
Hungry for revenge, she takes several needles of spine fluid to avoid changing again. Three months later Sue is still in control and there are ads for her New Year’s Eve show on TV and the billboard. One night Sue brings another man to the apartment, but she asks him to wait while she goes to the bathroom.
The hidden room is filled with trash yet Sue continues to extract fluid from Elisabeth without cleaning up. The injection wound is now infected and the liquid comes out looking dark and almost necrotic. Starting to feel dizzy, Sue calls the number and explains there’s no more stabilizer fluid, so the voice explains she’s drained it all out.
The fluid needs time to regenerate and for that Sue needs to switch bodies. She freaks out and refuses because her big show is the next day, however her nose starts bleeding and she collapses. Struggling with the pain, Sue has no choice but to crawl back to the bathroom and finally do the change.
In the bedroom, the man hears a noise and comes to the bathroom to investigate, but Elisabeth locks the door before he can see her. Ignoring his questions, she looks in the mirror and is horrified to discover an abomination. Furious, she yells at the guy to make him leave.
Afterward she comes out of the bathroom, and it’s so hard to walk in this body that she keeps on falling. Once she reaches the living room, she calls the number and chooses to cancel the experience. Then she brings her old poster out of the secret room.
The next morning, a black envelope arrives saying the last delivery is in the box. Elisabeth covers her body with as many clothes as possible and on her way out she yells at the neighbor, who immediately hides in fear. She runs to the alley to get the box and brings it home to open it, finding one single syringe with a black liquid.
Suddenly she hears a voice telling her there’s no going back, but she ignores it and injects the dark fluid into Sue’s body. However she also remembers that tonight is the big show and stops herself before emptying the syringe. Then Elisabeth giving Sue CPR, causing her nose to bleed.
Seeing it as a sign, Elisabeth gets the change kit and gives Sue some of her blood, which wakes her up. Strangely, Elisabeth doesn’t go to sleep. The women stare at each other in shock until Sue sees the termination syringe on the ground.
She immediately freaks out and chases after Elisabeth, kicking her against her big poster before pushing her against the broken glass to try to choke her. Elisabeth manages to grab a vase and breaks it on Sue’s head before running toward the bathroom. Sue tries to follow her and when Elisabeth locks the door, she repeatedly kicks it to open it again.
Next Sue kicks Elisabeth once more and forces her to look at them in the mirror before she starts smashing her head on it. After multiple hits, Sue drops the body and Elisabeth crawls away, only for Sue to send her flying with another kick. This time the kicking continues for several minutes until Elisabeth is finally dead.
Covered in blood, Sue realizes what she’s done and breaks down in tears, but this doesn’t stop her from remembering her show. That night Sue goes to the TV station and at the make-up chair, she starts coughing and hearing the screeching sound. She runs to the bathroom to spit in the sink and a tooth falls from her mouth.
To test the state of her body, Sue pulls two more teeth and they easily come out as well, which leaves her spitting lots of blood. After washing up, she meets with Harvey and the shareholders and offers a closed-mouthed smile. Then she gets in the elevator and presses a button, only to discover her nails are coming off as well.
At that moment, one of her ears lands right on her lap, but she has to play it cool because a man is entering the elevator too. Sue covers the hole in her head with her hand until the guy is gone. Afterward Sue leaves through the back door and runs back to her apartment, where she searches for the activator that was supposed to be used only once.
Hoping she can make a new beautiful body, she injects herself with the green liquid and falls to the floor in pain as her back splits open. Once the process is done, Sue checks the new body on the mirror and is horrified to discover a disgusting deformed creature with Elisabeth’s face on the back. This creature is Monster Elisasue and after throwing up the green liquid, she puts on the show dress and jewelry; she also curls the few hair strands she has.
Since it doesn’t help much, she decides to destroy the old poster to make a mask that she glues to her face and puts lipstick on. Then she goes to the TV station and is delighted to find everyone welcoming her with praising worlds, but this turns out to be her imagination. Since the lights are off in the main stage, Elisasue manages to get on it without being seen.
When the show begins, the lights are turned on and Elisasue tries to speak into the mic, but only mumbling comes out of her deformed mouth. At that moment the mask falls and she starts puking body parts, which everybody finds disgusting. After the initial shock, a woman screams and a man calls her a monster, causing the rest of the audience to freak out as well.
A bunch of guys surround her and being pushing her around while calling her things like “monster” and “freak”. Elisasue falls to the floor in tears, trying to speak to no avail. When she stands up, a man hits her with a baseball bat and decapitates her.
However her head slowly regenerates at the same time her arm falls off, causing a spray of blood that showers the whole crowd for several minutes. The entire room ends up covered in red and the people can barely move because they keep on slipping and falling against each other. Eventually Elisasue manages to escape the building, but as she’s running down the street she falls and her body explodes in thousands of gory pieces.
The only part still alive is Elisabeth’s face, which crawls out of the pile to reach her star. She happily stands on it and remembers the old days until she melts away. The next morning, a floor scrubber cleans off the blood as it was just another stain on the street.
