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The movie begins with an anonymous hand injecting a chartreuse liquid into the yolk of a raw egg, which splits and duplicates itself like a cell dividing. The scene switches to a movie studio, where Elisabeth Sparkle, a former Academy Award-winning actress, is in the process of committing the unforgivable crime of turning fifty. Because of this, she faces an abrupt end to her professional life. Elisabeth was a major Hollywood star for most of her career, and she has recently been hosting an aerobics television show. Despite the show’s success, its producer Harvey takes Elisabeth to lunch and —over a colossal portion of unshelled prawns—tells her she’s getting too old and fires her. Elisabeth is devastated by the rejection and drives aimlessly through the city. As she travels miserably through the streets, she sees a massive poster for her show being ripped off a billboard. Overcome with despair and unable to look away, she doesn’t stop at an intersection and is t-boned by another car. She’s miraculously uninjured. 

At the hospital where she is getting checked out, a young nurse surreptitiously hands Elisabeth a flash drive containing details about an underground product known as "The Substance." When Elisabeth watches the drive’s contents, she learns that The Substance is an illicit drug that promises anyone who takes it access to a youthful, flawless version of themselves. She tries to resist calling the number on the card, but because she’s desperate to reclaim her former beauty and career, Elisabeth gives in, orders The Substance, and injects it. After the injection, her body immediately begins to convulse, and she collapses. She writhes on the tiled bathroom floor as a younger version of herself wrests itself out of a tear that opens along her spine. The new, younger “Elisabeth” admires herself in the mirror before vomiting green bile on the ground. She stitches up the rip in the original Elisabeth’s skin. 

The instructions that come with the Substance explain that transformation requires that every user adheres to a strict schedule. Every seven days, the two bodies must switch places; the unconscious one wakes up, and the other becomes vacant. The inactive body, which remains unconscious and helpless, has to be nourished intravenously. The younger Elisabeth, who now calls herself “Sue,” also needs to extract fluid from the spine of her original body and inject it every day in order to “stabilize” herself. If she fails to follow the regimen, it’s implied she will collapse and die. Sue “stabilizes” herself and immediately auditions for Elisabeth’s former show. She impresses Harvey, who offers her the opportunity to host a show of her own and is willing to work around her “schedule conflict” every other week. The women begin to switch places regularly. As Sue thrives in the spotlight, Elisabeth retreats into isolation. She grows resentful of the person she has created. 

The tension rises between them when Sue, enjoying her new life too much to stop, delays the weekly switch by drawing extra stabilizer fluid from Elisabeth. This causes Elisabeth’s right index finger to age prematurely. It becomes gray and knobbly, a frightening warning of what could happen if Sue disrupts the seven-day process again. Elisabeth contacts the supplier of The Substance for help but only receives a stern warning that any further deviation from the schedule will cause irreversible, accelerated aging. Elisabeth and Sue begin to see each other as rivals. Elisabeth despises Sue for her recklessness and selfishness, while Sue loathes Elisabeth’s insecurity and self-destructive behavior. Sue decides to start extending her periods in the world so she can take on more work and go to more parties, damaging Elizabeth’s body more and more. Their relationship deteriorates further when Sue, unwilling to return to her former body, stockpiles stabilizer fluid for months at a time and refuses to switch back. Harvey promises Sue a once-in-a-lifetime role hosting a New Years’ Eve broadcast. 

Months pass, and Sue grows ever more famous as Elisabeth continues to age at an alarming rate. By the day before the New Year’s Eve broadcast, Sue has exhausted her stabilizer supply and has no choice but to switch back. When Elisabeth regains control, she discovers her body has turned into a crumbling and hideously aged wreck. Horrified by what Sue has done to her, Elisabeth resolves to stop the cycle before she gets any older. She orders a serum from the makers of The Substance designed to eliminate Sue permanently. However, when she tries to inject it, she hesitates before pushing the plunger. The thrill of Sue’s celebrity status and the glamour of her new life prove too tempting to give up. Instead of finishing the injection, Elisabeth, weeping, revives Sue. Both of them are now conscious at the same time. Quickly realizing that Elisabeth attempted to destroy her, Sue retaliates. She violently kills Elisabeth and leaves for the New Year's Eve show.  

However, without the original body providing stabilizer fluid, Sue’s Substance-generated body rapidly begins to fall apart. As her body disintegrates, Sue desperately attempts to generate another youthful version of herself using a second dose of the activation serum. However, by violating the instruction that the serum can only be activated once, Sue accidentally creates a grotesque, mutated monster. This character—“Monstro Elisasue”— bears both Elisabeth and Sue’s features but is mostly a misshapen and hideous blob of flesh. Maddened but determined to maintain her fame, Monstro cuts out a mask from a poster of Elisabeth’s face and returns to the studio, attempting to perform the broadcast. The sight of her horrifically mutated body sends the audience into panic. Chaos erupts, and an audience member rushes forward and decapitates her. Instead of dying, Monstro just regenerates an even more grotesque head from the stump of the previous one. Her body collapses, then she explodes in a violent and prolonged burst of gore; the whole theater becomes a blood-soaked hellscape. She flees the scene, crumbling into a pile of gore as her body disintegrates. 

Elisabeth’s original face detaches from the remains and moves on its own. It laboriously hefts itself over to her star on the Hollywood Walk of Fame. “Elisabeth” grins as she imagines herself basking in admiration one final time before dissolving into a pool of blood. By the following morning, all traces of her existence are erased when an industrial cleaner polishes the star.

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