The film opens with Madeline Ashton (Meryl Streep), performing on Broadway in an elaborate dance number. In attendance in the audience are her childhood friend, Helen Sharp (Goldie Hawn), and her fiance Ernest Menville (Bruce Willis). Helen shortly after feels that Ernest has fallen for her friend's glamorous charms, and her fears soon prove to be correct, when their engagement falls apart, and Ernest marries Madeline.
This causes Helen to fall into a depressive spiral, in which she gorges on ready made cans of frosting and becomes obese, living in an apartment with numerous cats. Her days generally consist of her watching a film starring Madeline, in which her character is killed, with Helen rewinding this scene over and over again. After she is evicted for failing to pay rent, Helen is put into a mental institution, but even after several months of therapy, she still has not shown any improvement. Her psychologist (Alaina Reed Hall) advises Helen that she needs to completely eliminate Madeline from her mind. In a twisted way (unknown to the psychologist), Helen takes this advice to heart.
During the this time, Madeline Ashton's career has slowly waned. Now obsessed with holding onto her once youthful looks, and having an affair with a younger man, which is not unknown to Ernest. Ernest meanwhile has become an alcoholic mortician and is miserable in his married life.
One day, Madeline receives an invitation for her and Ernest to attend a book release party from Helen. Madeline goes, eager to see Helen as an overweight woman... only to find her old friend now a svelte, and beautiful woman.
Helen's 'rejuvenation' causes Madeline to slowly lose her mind. After she angrily chews out her spa technician, the owner of the spa gives Madeline a business card to someone he claims can help her. The card he gives Madeline translates to Street of Flowers in French. Madeline just scoffs at this, and goes to see her young male lover...only to find that he's cheating on her! Now more upset than ever, Madeline then looks at the card she was given, and goes to see Lisle von Rhuman (Isabella Rossellini).
Lisle resides in a large, Gothic mansion, and reveals to Madeline a potion that will restore her youth and make her live forever - however Lisle isn't too clear on that last point, simply telling Madeline to "Take care of your body since you would be together a long time". Madeline eagerly takes the potion, holding it over her mouth to get every last drop. Before she leaves the mansion, Madeline looks in a mirror, and is amazed to see her wrinkles disappear, and her body become taut and firm again. She remarks to the guard "I'm a girl!" and the guard simply puts his finger to his lips, indicating the level of secrecy Madeline must now adhere to.
Meanwhile, Ernest has been visited upon by Helen, who attempts to seduce Ernest into helping her kill Madeline. Her plan is simple: After drugging Madeline, they'll stage a drunk driving accident starring Madeline that will get Madeline out of both of their lives.
Helen leaves shortly thereafter, and Madeline returns home, happy to be youthful again. Feeling better than before, but having been tempted by Helen's plans, he ends up pushing Madeline down the stairs instead of saving her after Madeline repeatedly calls Ernest flaccid. Unsure what to do next, Ernest places a call to Helen, revealing their plans as he thinks Madeline dead... only to find Madeline revived, with her head twisted backwards! After straightening her head, the two then go to the local hospital.
While there, the doctor is surprised when his stethoscope picks up no heartbeat, and no pulse, which would technically mean that Madeline is dead. Ernest goes out for a little bit, only to return and find they've taken his wife to the Morgue. After finding her there, Ernest declares that Madeline is some kind of miracle, and decides to take care of her. It seems he totally forgot Helen's plans. But Helen hasn't!
Returning to the mansion, Ernest notes that Madeline has lost color, and goes to the mortuary where he works to pick up formaldehyde, tubes, paints and other things. He then paints her body and does her makeup. However, this process is interrupted by Helen, who has come in regards to Ernest's panicked call to her reporting Madeline's lethal (he thinks) fall down the stairs.
As their voices get higher, Madeline overhears Helen's intended death plot for her, and appears before the two, brandishing a shotgun. Madeline ends up blowing Helen into the garden pool with a gaping hole in her abdomen. Ernest is freaked about having a dead body on his hands (again), but gets another shock when Helen emerges from the pool, still alive, save for the hole in her stomach.
As Ernest watches, the two women then accuse the other of taking Lisle's potion, and then engage in a shovel battle, at which point Ernest goes back upstairs.
During the fight, the two end up hurting each other physically, but then begin to lay out their own emotional feelings...before finally coming to a reconciliation. Going to Ernest, they say they have made up, and ask him to fix them. Ernest agrees, but on the condition that he is allowed to leave them forever once he has finished. The girls agree immediately to never contacting him again.
After repairing the girls, they are at first overjoyed, but then realize that their bodies require upkeep now, and only Ernest can provide that. Helen suggests they drug him, and both girls attempt to have Ernest drink an alcoholic drink with a drug in it. However, Ernest then considers that he drinks too much, and refuses. In desperation, the girls hit Ernest over the head, knocking him unconscious.
Ernest wakes up in the swimming pool area of Lisle's mansion, dressed in a tux. Lisle is swimming and steps out of the pool naked but for a long scarf and high heels. (Note: this is a naked body double, and not Ms. Rossellini.) Lisle is throwing a party for her clients tonight, but has taken time to meet with Ernest at Madeline and Helen's request. Lisle shows Ernest the effects of the potion, and encourages him to take it as well. However, Ernest is reluctant, seeing a downside to living forever: he'll watch all the people around him get old and die, and most likely end up having to cope with Madeline and Helen forever.
Ernest attempts to escape, but first encounters Lisle's party (at which Greta Garbo, Jim Morrison, Marilyn Monroe, Andy Warhol, Elvis, and James Dean are just some of the attendees). Ernest runs away with Helen and Madeline, as well as the guards Tom, Dick and Harry, in hot pursuit. Ernest ends up dangling precariously above the glass windows over the swimming pool, where Helen and Madeline find him. Ernest still has the potion in his possession, and the two at first plead, but then demand that he take the potion.
Realizing his 'importance' to them, Ernest drops the potion, and explains to the girls, "You're on your own," before plummeting into the glass and the pool below. There he encounters Jim Morrison with a woman who is taking off her clothes prior to swimming. After Ernest falls through the stained glass ceiling and lands safely in the water, Jim Morrison asks him if he's done with the pool yet. Ernest assures him that he is done!
Ernest escapes the mansion in a vintage Porsche (which belongs to James Dean). Helen and Madeline, acting on Lisle's orders, attempt to track Ernest down, first returning to Madeline's place, only to find Ernest has already packed and headed for the airport. It is then that they realize that they are now stuck with each other.
37 years later, Ernest finally dies, and a funeral is held for him. The preacher (who you may recognize as the preacher from the film by David Byrne/Talking Heads entitled True Stories) eulogizes about Ernest's accomplishments in those last 37 years. In the time he had left, Ernest made more of his life than he had previously, becoming a mountain climber, remarrying and having 6 children with his 2nd wife, starting clinics for alcoholics, as well as one to understand and study women and their behaviors. During the sermon, the preacher claims that Ernest has obtained true immortality through his family, and the lives of those he had touched through his generosity and giving nature. The preacher even mentions Ernest the Prankster's long time "jokes" about the living dead in Beverly Hills.
In the back of the church, Helen and Madeline, wearing heavy black veils to cover up their faces, are listening, and upon hearing this, Madeline mockingly says, "Blah blah blah blah blah blah," and the girls exit the church.
Outside, the two women (whose faces look far, far worse due to their constant touch-ups), begin to argue, before Helen accidentally slips on a can of spray paint she dropped. Helen is in danger of falling down the chapel steps, with Madeline just smiling smugly. However, Helen isn't going down alone, and grabs her 'friend.' The two of them tumble down the stairs, before their bodies shatter into various pieces at the bottom.
In their shattered state, Helen's decapitated head asks Madeline's head the one thing that is now on her mind: "Do you remember where you parked the car?"