A Little Life explores the tragic life of Jude St. Francis. The plot is conveyed through flashbacks and retrospective narration. Jude is abandoned at a monastery in South Dakota as an infant and raised by the priests there. They are generally cruel and abusive towards him, and when one priest, Brother Luke, takes a special interest in him, Jude initially feels grateful for the affection. When Jude is 11, Brother Luke abducts him from the monastery. They spend years on the run, crisscrossing the country. During this time, Luke both repeatedly rapes Jude and offers him to other men to have sex with in exchange for money. One day, in Montana, police raid the hotel room and attempt to arrest Brother Luke, though he hangs himself before they can detain him. Jude is transferred to foster care, where he continues to experience physical and sexual abuse. When he is fourteen, he runs away and attempts to hitchhike to Boston alone. Along the way, he becomes very sick and ends up being abducted by another sadistic man, known as Dr. Traylor. Traylor holds Jude captive, raping him repeatedly, and eventually running him over with a car. The injuries Jude sustains in this incident leave him with permanent disabilities and lifelong pain.
However, in the hospital, Jude encounters a sympathetic social worker named Ana, who encourages him to plan to go to college. At college, Jude becomes part of a circle of close friends along with Willem, an attractive aspiring model, JB, a painter from a Haitian family, and Malcolm, an architect from a wealthy family. Jude feels closest to Willem because, like him, Willem is an orphan who did not grow up in a wealthy family. After graduation, Jude and Willem move in together in a shabby apartment on Lispenard Street in New York City. Jude is beloved by his friends but is also very secretive about his past; he never reveals the source of his disability, nor the fact that he regularly engages in self-harming behaviors as a way to cope with his past trauma. The only person with whom Jude is fully honest is his doctor, Andy. Andy helps to protect Jude's secrets and does his best to care for him.
In the years post-graduation, the careers of all four men gradually advance. Jude attends law school, where he attracts the attention of a professor named Harold. Over time, Jude becomes close with Harold and his wife, Julia. Since Harold and Julia grow to love Jude like their son, they eventually end up formally adopting him. Jude initially begins working as a public defense attorney but eventually takes on a much higher-paying role at a corporate firm. Secretly, Jude knows that his health is deteriorating, and he wants to ensure he always has enough income to live in comfort. Meanwhile, Willem's career as an actor has taken off, and he and Jude remain very close. In contrast, Jude's relationship with JB gradually breaks down: Jude is hurt when JB exhibits paintings of Jude without asking for his consent, and later on, as JB succumbs to drug addiction, he cruelly mocks Jude's disability. Although JB apologizes, Jude is never able to forgive him.
Throughout his 30s and 40s, Jude lives a double life. He has many close and loving friendships, notably with Willem, and unconditional love and support from Harold and Julia. His career is extremely successful, and he earns a lot of money. At the same time, he lives with constant physical pain and psychological trauma. He has never revealed anything about his past to anyone, he regularly self-harms, and he lives in constant dread that someone he cares about will find out about his past. Although Jude has never been in a romantic relationship, when he meets an attractive fashion designer named Caleb, he tentatively begins a relationship. However, Caleb becomes horribly abusive, beating and raping Jude. Harold eventually discovers what has happened and also realizes that Jude has been cutting himself. Harold and Andy keep Jude's secret about what has happened, but the trauma of what he experiences with Caleb leads Jude to attempt to commit suicide.
Jude survives his suicide attempt, and Willem, who has been somewhat preoccupied with his career and frequent travels, realizes that his beloved friend needs more support. Willem moves in with Jude and eventually admits that he is in love with him. Jude reciprocates some of these feelings, but navigating the relationship is difficult for him. He hates having sex and resents Willem asking him about his past. Willem eventually finds about Jude's self-harming, and this leads to many conflicts between the two of them, along with Jude escalating his dangerous behavior. Eventually, Jude tells Willem the full story of all the abuse and trauma he suffered as a child and adolescent. He also admits how much he hates sex. After this, Jude and Willem stay together as loving companions, but they no longer have a sexual relationship.
Jude and Willem have years of relative happiness together, but as Jude grows older, his injuries cause him more and more pain. Eventually, he has both legs amputated. Even then, there are many happy moments because of his friends, family, and career. However, when Jude is in his early fifties, Willem, Malcolm, and Malcolm's wife, Sophie, are all tragically killed in a car accident. After the accident, Jude's mental health deteriorates rapidly. Andy and Harold try to help as best as they can, but in the final section of the novel, Harold reveals that Jude killed himself 2 years after Willem's death, at age 51.
