Valley of the Dolls centers on three primary characters: Jennifer North, Neely O'Hara, and Anne Wells. Jennifer is stunning yet lacks talent, but her beauty alone catapults her to fame. Despite this, she is not interested in being a celebrity. Her mother instilled in her the importance of financial security, constantly reminding her of the economic burden she placed on the family and the necessity of marrying well. Jennifer doesn't truly value money. She is restless with it, frequently purchasing new clothes only to give them away, never accumulating wealth. Her quest for financial stability leads to two unsuccessful marriages. Jennifer finds happiness only twice: first with her lesbian partner, until Maria becomes overly possessive, and later with a senator. Jennifer is inherently good-hearted. She conceals her husband's mental illness to protect his career and decides to secretly abort her child to prevent passing on the father's disability. Jennifer embodies a sense of aimlessness, lacking focus and direction. In many respects, she is the book's most endearing character, possessing an innocence and sweetness, as Anne describes. However, Jennifer is not particularly intelligent.

Neely O'Hara begins as an unrefined, carefree youngster, raised by her brother on the vaudeville circuit, where she performs in his act. While Neely is attractive, she isn't a classic beauty, but she is the most gifted performer of her time. She remains lively and charming until she arrives in Hollywood. There, she transforms into a star with monstrous tendencies. The relentless work schedule, leaving no room for anything beyond her career, drives her to alcohol and drugs. Her ego becomes massive and unpleasant. Her insecurities lead her down a path of self-destruction, resulting in multiple suicide attempts and a stay in a sanitarium. Yet, she always manages to make a comeback. As Lyon observes: "It's like a civil war, with her emotions battling her talent and physical strength. One side has to surrender. Something must be sacrificed."

Anne Wells hails from New England and is characterized by her upbringing and manners. She is empathetic and a loyal friend, known for her honesty. Her character seems almost too good to be true. Her only flaw is her love for Lyon Burke. She will do anything for him, except return to her small-town roots. Consequently, she loses him and spends the next fifteen years in an unsatisfying relationship, becoming wealthy and famous. When Lyon returns, she manipulates him into marrying her. Anne cannot stop loving Lyon, even after he cheats on her with her closest friend. However, by the novel's conclusion, she feels her affection for him waning and realizes that one day she will no longer love him. She begins using "dolls" (pills).

Susann possessed an understanding of depravity, yet she lacked a perception of evil. Her characters are not inherently wicked. While they might meet unfortunate ends, they begin as good individuals. This absence of an evil sense might raise moral questions, but it lends her character portrayals a distinct sharpness often absent in mainstream fiction. It's a peculiar type of Freudian narrative; her characters have their motivations. It is the narrative of victims.