Jacqueline Susann (BETTE MIDLER) is a middle-aged woman who just wants to be famous. Despite some work in the theater and on the radio, she feels that she's passed her prime and missed the opportunity for fame. Thus, when publicist Irving Mansfield (NATHAN LANE) shows up and not only states his intention to take her on as a client, but also as his lover, Jacqueline is shocked.
Even so, she's thrilled when he lands her a national TV commercial contract as well as an appearance on a game show. Yet, those jobs don't manage to propel Jacqueline to the top and that, coupled with their having to institutionalize their toddler due to his autism, puts her into a tailspin that not even her best friend, actress Florence "Flo" Maybelle (STOCKARD CHANNING), can break.
It's not long, however, before Irving has come up with another idea, this time for Jacqueline to become a novelist. Although she's initially reluctant since she claims she knows nothing except for the sex and drug related activities of the entertainment world, she and Irving realize that would be the perfect fodder for a trashy novel.
As such, Jacqueline begins writing "The Valley of the Dolls," a risqué and amateurish novel that no publisher wishes to touch. That is, except for Henry Marcus (JOHN CLEESE), who assigns straight-laced editor, Michael Hastings (DAVID HYDE PIERCE), to work with Jacqueline in refining her work. Although their styles clash, the two finally achieve their goal and, with Irving's help, begin promoting her book. As Jacqueline progressively gets closer to attaining her dreams of global fame, she must contend with criticism of her work, a secret battle with breast cancer, and her own self-doubts.