Content warning: The following summary contains references to sexual abuse, rape, self-harm, and suicide. 

The novel’s first section introduces the core friend group in the years immediately following their time together in college. Malcolm, JB, Jude, and Willem were college roommates in Hood Hall at an unnamed university in Boston and they now live in New York City. Jude and Willem share a shabby apartment at Lispenard Street, JB shares apartment space with a decadent and wealthy artist friend, and Malcolm still lives at home with his parents. Malcolm is irritable because he is frustrated by perceived signs of success among his friends while struggling to realize his own talent. JB, encouraged by his doting family, is certain of his artistic career. Willem and Jude are grateful for the chance to compete among their peers and earn their way in the world.  

By the second section, Jude St. Francis emerges as the protagonist of A Little Life. JB nicknames Jude the “post-man,” meaning that he is beyond race, ethnicity, religion, and perhaps even experience. Jude’s interior narrative, however, reveals a keen sensitivity to all of life, especially as it touches upon his identity, about which he feels guilty and indeterminate. As an abandoned infant, he was taken in by a monastery, where he was routinely verbally, physically, and sexually abused. An accident as an adolescent left him unable to walk and put him in the hands of a social worker named Ana. She encourages him to talk about what happened to him before he internalizes it, but she dies before he does so. Instead, Jude cuts himself to cope with his trauma and must visit Dr. Andy Contractor regularly to have his wounds tended. He attracts other mentors through law school, including Harold Stein. 

Harold met Jude as a law student, and while Harold was dazzled by the young man’s intellect, the professor was in genuine awe of his moral arguments. Over time, he sees these fade from Jude’s professional career, but more importantly, from his thought process, a loss that Harold mourns and for which he feels partly responsible. Jacob, Harold’s son, was diagnosed at age 4 with a rare disease from which he died at age 6, which helps to explain why he and his wife Julia decide to adopt Jude as a 30-year-old man. The adoption day is marred only slightly by the absence of JB, who angers the friend group by exploiting Jude for a work of art. Jude suffers painful episodes in his legs and spine, resulting from the venereal diseases to which his childhood exposed him. JB photographed him in one such episode and painted it for an exhibition. Jude is furious, and Willem is unforgiving.  

Jude changes his career path from the U.S. Attorney’s office to an obscenely wealthy private firm, but he refuses to take the accompanying financial advantage of the job until the elevator at Lispenard Street gives out, again. Jude’s friend Richard owns a semi-private apartment building in which Jude purchases a floor. Jude is increasingly grateful for Willem’s presence in his life, especially as JB is now absent again, this time due to drug use. The friends try to intervene, but JB’s darker side prevails. His mocking of Jude’s disability proves more than any of them can handle, but JB is at least confined to the hospital and removed from the drug scene. The friends next see one another at Malcolm’s wedding to Sophie, but the scene is tense as JB is still not forgiven.  

Willem leaves for a long film shoot, and Jude, left alone, meets Caleb Porter. The two start an intimate relationship that quickly turns violent and demeaning. Caleb is disgusted at Jude’s disability and delights in torturing him. In one particularly brutal scene, Caleb throws Jude naked onto the streets of New York City, retrieves him, beats and rapes him repeatedly, and finally kicks him down a long flight of stairs, leaving Jude with broken arms and ribs and a host of memories from which he cannot escape. He relives his childhood with Brother Luke, who abducted a then eight-year-old Jude from the monastery and forced him into prostitution to earn a living while carrying on a sexual relationship with him. The weight of so much trauma becomes overwhelming, and Jude tries to take his own life. He wakes up in the hospital, surrounded by friends, whom he feels he has disappointed.

In the Happy Years, Willem and Jude are finally in the romantic relationship which they both have longed for, but unbeknownst to Willem, their sexual relationship is torture for Jude. He reacts by cutting himself more frequently, a behavior which his friends work valiantly to help him overcome. Jude responds by burning himself instead, forcing Willem to realize that Jude is truly mentally ill, and that they cannot continue having a sexual relationship, especially after Jude finally tells Willem the whole story of his childhood. Brother Luke was eventually discovered by the police, and Jude was sent to a home in Montana. There, he is again sexually abused and beaten brutally. At 15, he runs away for Boston, hoping to somehow get into college, hitchhiking and paying with the only currency he has. But he falls ill, and Dr. Traylor abducts him, keeping him in a basement until the doctor tires of him. Then, the doctor drives Jude to a field, lets him loose, and chases him with the car, running him over and leaving him to die.   

As the other three friends attain the pinnacles of their careers, Jude must decide when to have his legs amputated. He and Willem celebrate their 50th birthdays, and shortly thereafter Willem, Malcolm, and Sophie die in a car crash. Jude copes only by holding desperately onto every shred of Willem he can piece together and by practicing kindness with his friends and family. Still, he stops eating and pretends as though he’s not starving himself to death until his friends and family intervene and strictly monitor him. In the final section, Harold describes Jude’s final, successful attempt to take his own life.