The Valley of the Dolls is a novel about the friendship between three women, the perils and rewards of fame, and chemical dependency. The story spans twenty years, from 1945 to 1965, and is set primarily in New York City. Anne Welles, Neely O'Hara, and Jennifer North become friends and roommates, find fame, get married and take lovers, and turn to drugs to cope with problems they encounter.

1945

At age nineteen, Anne Welles leaves her hometown of Lawrenceville for the excitement of New York City. She goes to work at the theatrical law firm of Bellamy and Bellows, and quickly becomes indispensable to its head, Henry Bellamy. She rents a modest room at a boarding house, where she meets the teenage Ethel "Neely" O'Neill, a struggling dancer. Anne is courted by Allen Cooper but falls in love with Lyon Burke, a former employee of Henry Bellamy's who has returned from fighting in World War II. Jennifer North, a model who breaks into acting despite the fact that she cannot sing, dance, or act, is a client.

Neely is hired as a dancer in a show starring Helen Lawson, a famous actress who is also a client of Bellamy and Bellows, but ends up as the understudy to a major role. Helen Lawson decides that the actress in that role is drawing attention away from her and manages to get her to quit. When Neely takes over, she is a critical success; her career takes off.

Allen Cooper reveals to Anne that he is a millionaire who kept his wealth secret to make sure the woman he proposes to says yes for him and not for his money. Anne does not want to marry him but he talks her into wearing his ring and considering marriage. Regardless, Anne and Lyon Burke become lovers on a business trip. A misunderstanding between them leaves her stranded away from home. When she turns to Jennifer North for help, the two girls become friends.

The three women enjoy a moderate success and become roommates. Neely leaves first to marry and move to California to pursue a film career; Jennifer marries the famous singer Tony Polar and moves to California with him and his sister. Lyon will not marry Anne until he can support them both as a writer, but they spend all their nights together. All three relationships dissolve. Neely leaves her husband for her costume designer. Jennifer, bored in California while her husband advances his career, starts to take drugs to pass the time and help her sleep. She learns that her husband is retarded from a condition he will pass on to any children, and aborts the child she is carrying. Anne inherits her mother's house and Lyon wants to move there to write, but Anne hates Lawrenceville so much that she will not consider it. He goes to England to write a book about the war.

1948

Anne leaves her job at Bellamy and Bellows to be the exclusive representative of Gillian Cosmetics. She is the "Gillian Girl", and the position makes her rich. She ends up in a passionless affair with the much older Kevin Gillmore, the owner of Gillian Cosmetics. Jennifer takes up with a French director and goes to Europe to act in adult-themed movies that show her nude. Still unable to act but fluent in French, she becomes famous for her beautiful body.

1950

Pressured by the demands of fame, Neely turns to drugs and alcohol to help her stay thin, sleep, and cope with stress. She sleeps through her twin sons' first birthday party and ruins her second marriage, too. She is dropped by her studio because she delays production so much that her films are not profitable (even though they are popular). She attempts suicide as a way to manipulate the studio into keeping her at star status, but finishes her contract without making any more movies.

1957-1961

Jennifer falls in love with a senator and looks forward to starting a family. A gynecological checkup reveals that she has breast cancer; she is advised to have a mastectomy and a hysterectomy. She starts to tell her fiancé that she can never have children because of the cancer, but he cuts her off. He tells her that he considers her breasts his babies. She commits suicide rather than be disfigured. Neely comes for the funeral and stays with Anne. She loses the ability to sing for psychological reasons. In a moment of self-pity she attempts suicide again. This time, Anne has her committed to a psychiatric institution, where Neely will stay for several years.

Lyon Burke returns to New York City from London for a writing assignment and encounters Anne. They decide to spend as much time together as possible, despite the fact that Anne is engaged to Kevin. Anne makes no attempt to hide her renewed interest in Lyon. Kevin finally breaks it off with her. With her friend Henry Bellamy's help (and without Lyon's knowledge), Anne manages to secure some longer-term writing projects for Lyon that keep him in New York City.

Henry's retirement from Bellamy and Bellows enables Anne to keep Lyon in New York City permanently. Anne secretly gives Henry enough money for him to loan to Lyon (under the pretense that it is his money) so Lyon can afford to buy Henry's share in the business. Lyon gives up writing to resume his position at the renamed Bellamy, Bellows, and Burke, assuming that Henry is helping him so the firm will not be bought by a rival.

1962-1965

Anne and Lyon marry and have a baby girl. Neely is released from Haven Manor and becomes a client of Bellamy, Bellows, and Burke. She demands more and more of Lyon's time, so Anne and the baby spend much of their time alone. A newspaper item alerts Anne that Lyon and Neely are having an affair. Neely tells Lyon about how Anne really is the one who bankrolled his purchase of the company. He vows to Anne that he will pay her back every dime but that he will no longer be controlled by her. Anne turns to Henry for support; he tells her to stick it out and gives her pills to help her cope. She finds work on a television program and keeps busy during the day; she takes Seconal at night to sleep.

Lyon and Neely carry on for several years, but break up when she becomes too demanding for him. Neely leaves Bellamy, Bellow, and Burke for a rival. Anne discovers Lyon and a young client kissing in a bedroom during a party, and realizes that although she still loves him, with every affair she will love him less until there is nothing left.