Since 1978 when her last Broadway gig fails, 14 years later Madeline still struggles with her fading looks and bygone acting career. Ernest, now an alcoholic and miserable in his marriage, has been reduced to working as a high-end mortician. Reveled at a book party,Helen, meanwhile, has become an established author with her book "Forever Young". When Madeline and Helen meet again at Helen's book-signing party, Helen appears miraculously rejuvenated, thin, and youthful.
After a failed attempt to spend the night with her young lover "So go find someone your own age Madeline", a jealous and hurt Madeline resorts to the aid of the mysterious Lisle von Rhoman (Isabella Rossellini), who claims she has discovered the secret of eternal youth. She offers Madeline a magical potion to reverse the process of aging, on condition that, after 10 years, Madeline must disappear from the public eye forever to protect Lisle's secret. Madeline purchases the potion at a very high price, drinks it, and is delighted to see her body visibly losing the signs of aging as she watches in a mirror, leaving her thin, firm, and young. Lisle then warns Madeline to take perfect care of her new body giving her the pin of simfile viva, live forever.
Helen, meanwhile, seduces Ernest and reveals to him a detailed and foolproof plot to kill Madeline, by poisoning her with narconal a powerful alcohol based tranquilizer. After she dies they plan on placing her in a car on Mulholland Drive faking a drunk driving accident. After some initial qualms, Ernest realizes that this can finally free himself of Madeline, and agrees to the conspiracy.
Back at home, Madeline is confronted by an angry Ernest, whom she rejects in her newly restored youth and confidence. He loses control and begins to grapple with her, until they reach the head of their grand staircase. Madeline teeters, then asks Ernest for help; however, when he waffles, she cannot help calling him a wimp in the process. In response, Ernest pokes her with a finger, sending her tumbling down the staircase. She breaks her neck and dies, with her neck twisted backwards.
While on the phone with Helen, Earnest gets advice on how to make it look like an accident. Suddenly, Madeline wakes up. After literally getting her head on straight, Madeline is rushed to the emergency room, where the doctor (an uncredited Sydney Pollack) tells her she has three fractures in her wrist, broken two vertebrae, has a body temperature below 80 degrees, and her heart's stopped beating. He rushes out of the room and dies of a heart attack after realizing that Madeline's physical body has died, even though she is still walking and talking. Returning home, Ernest uses his mortician skills to repair the damage done to Madeline's body.
Helen then reappears at their home to bury Madeline - whom she thinks is dead - in Death Valley. A livid Madeline overhears the plot, and then confronts Helen with a single shotgun blast to the stomach saying, "I just want you to know one thing, You brought this on yourself", killing Helen who flies into the pond on the terrace. However, despite having a large gaping hole blown through her abdomen, Helen reawakens; Madeline guesses correctly that Helen was also a customer of Lisle's. As the two undead rivals fight (failing to do any real damage or even inflict pain on each other), Ernest decides to leave them both.
Eventually reconciling their differences, admitting Helen thought Madeline was cheap and Madeline hurt Helen on purpose. Madeline and Helen beg Ernest to repair their incredibly damaged bodies. Ernest agrees, but his repairs are only temporary: Madeline and Helen will need Ernest to perform routine maintenance to their bodies forever. They then conspire to make Ernest drink the potion as well, knocking him unconscious and taking him to Lisle as he tries to leave them. Although Lisle makes an impassioned argument for immortality, showing him a sample of her work on his aging hand, Ernest refuses the potion stating how a life lived forever is worthless because your friends would all die before you and boredom would be inevitable. As he flees through Lisle's labyrinthine mansion, he encounters many celebrities generally assumed to be dead, including Marilyn Monroe, Greta Garbo, Andy Warhol, Elvis Presley, James Dean and Jim Morrison. In trying to escape he finds himself on the roof of the house, trying to get to an exit on the other side of a tower, when Madeline and Helen suprise him by running onto the roof as well he slips and his suspenders stick onto the ran gutter braking it off and swinging him over an open pit. Unwillingly dangling by his suspenders from a damaged portion of rain gutter. Madeline and Helen implore one last time him to drink the potion so he will survive his inevitable fall. Ernest refuses again, lets the potion fall, then falls off the roof and into Lisle's swimming pool. Cushioned and saved by the water landing, he steals James Dean's car, escaping for good. With Ernest gone, Helen and Madeline realize, much to their chagrin, that they are now forced to take care of each other...forever.
Thirty-seven years later (2019), Ernest has died; Madeline and Helen attend his funeral, using veils to cover their horribly deteriorated forms. Ernest is eulogized as having lived a good and adventurous life, accomplishing much more in his mortal lifespan than Helen and Madeline are ever likely to do in their self-centered immortality. Throughout the service, Madeline and Helen bicker endlessly, but look up at the priest when he describes Ernest as having attained eternal life and youth through his accomplishments, his good works, and his children and grandchildren who carry on his name. Faced with an alternative concept of immortality, Madeline and Helen mock the priest with Madeline saying "blah blah blah" and leave.
Outside the church, Madeline and Helen continue to bicker over a lost bottle of spray paint. Helen then slips on a can of spray paint and begs Madeline for help. Madeline wont help Helen due to the argument over how forgetful she is and Helen falls, taking Madeline down with her. Tumbling down another long flight of stairs, the two literally shatter to pieces at the bottom. Helen's tottering, decapitated head then queries, "Do you remember where you parked the car?" as the screen cuts to black.
I think it's tedious. Whatever concentration you can apply to that kind of comedy is just shredded. You stand there like a piece of machinery— they should get machinery to do it. I loved how it turned out. But it's not fun to act to a lampstand. 'Pretend this is Goldie, right here! Uh, no, I'm sorry, Bob, she went off the mark by five centimeters, and now her head won't match her neck!' It was like being at the dentist.