The story takes place in a world in which everyone is turned "stunningly attractive and blissfully carefree" — a "pretty" — by major cosmetic surgery at the age of 16. The operation also creates lesions in the brain. These lesions prevent dispute, anger, creativity, and wanting to be different. The people who first founded New Pretty Town, Uglyville, etc. created the operation and the brain lesions to help prevent war and anger...which had caused the extinction of the "Rusties". Living in a world of diminished resources and high technology, a reduced population has retreated into relatively few cities after an unremembered global catastrophe, leaving behind the "Rusty Ruins" of decaying cities in the abandoned stretches of countryside. Society is structured into a rigid system of littlies (children), uglies (adolescents), new pretties (teenagers and young adults), middle and late pretties (adults), and crumblies (retired adults). The city governments administer the cosmetic surgery to foster conformity, purging humanity of ruinous competition and jealousy. Until the operation, uglies attend school away from their parents, living in dorms in Uglyville. After the operation, they leave Uglyville and move to New Pretty Town to begin living privileged lives centered on leisure and entertainment.
The book starts out with Tally Youngblood, a girl who is about to turn sixteen, looking forward to becoming "a pretty." While waiting for her birthday, Tally becomes friends with another ugly, Shay, who shares her birthday. Shay, however, has contacted rebels who live outside government control in a hidden refuge called the Smoke. She doesn't want to become a pretty, and instead escapes to the Smoke just prior to her birthday. When Shay invites Tally to come to the Smoke with her before she leaves for the Smoke, Tally refuses to join her. Shay leaves alone but gives Tally a note of cryptic clues to the Smoke's location, should Tally change her mind. Tally then promises never to reveal the Smoke's whereabouts.
Tally's excitement about becoming a pretty disappears when her operation is delayed with an ultimatum from the city's secret police organization, Special Circumstances. A "special", Dr. Cable, tells Tally that she can't become a pretty until she reveals Shay and the Smoke's location. Forced by Special Circumstances to find and infiltrate the Smoke using Shay's directions, Tally changes her mind about becoming a pretty shortly after arrival and meeting its leader, David, with whom she starts to fall in love. She learns from his pretty parents, Maddy and Az (who no longer have lesions), that the pretty operation does more than just change appearances: more specifically, it makes people docile and more compliant with authority by creating lesions in the brain. Despite Tally's effort to stop Special Circumstances from arriving at the Smoke, they track her anyway, destroying the Smoke and capturing all but Tally and David.
Tally and David mount a successful rescue operation on the Special Circumstances headquarters, returning with their friends to an abandoned Rusty Ruins city. David's dad (Az) has died and Shay had turned into a pretty with lesions in her brain. Maddy discovers a cure for the lesions but Shay refuses to take them. Tally decides to sacrifice herself for Shay. Maddie wants to cure the "lazy vanity" created by the surgical brainwashing done to pretties, but needs a willing subject to test its efficiency and safeness. Tally volunteers to return to the city to undergo the pretty operation and then be the test subject. The story closes as Tally turns herself in to the city authorities, saying, "Make me pretty."