A Million Little Pieces opens with the narrator, James, waking up on an airplane with no idea where he is going. He has a hole in his cheek, four broken teeth, and a broken nose. James eventually finds out that the plane is bound for Chicago and that a doctor and two unidentified men brought him on board. James lands to find his parents, who have come all the way from Tokyo to pick him up, waiting for him. James’s condition shocks and saddens them, and they immediately drive him to the family cabin. They next day, they check him into a rehabilitation facility in Minnesota. Almost immediately after arrival, another patient pulls James to the floor when James refuses to give up his seat in the lounge. Things improve somewhat when James meets a young woman named Lilly at the dispensary and a friendly, middle-aged career criminal named Leonard at a meal. Both become his friends.

Near-constant vomiting and pain mark James’s early days at the clinic. To fix his broken teeth, James submits himself to a horrific double root canal without Novocain. James decides that his condition is hopeless and walks out of the clinic, but Leonard follows him and convinces him to stay. James’s brother Bob and two friends show up at the clinic unexpectedly for visiting day and bring some gifts. This show of kindness moves James deeply. After Bob leaves, James’s parents call him and ask if he’ll do the Family Program, during which they would come to the clinic and engage in counseling sessions with him. He says he doesn’t want them to come. James begins reading the Tao Te Ching, and it greatly inspires him. For once, James has found something that makes sense to him, something that speaks of self-reliance. Though he knows that the clinic staff is trying to help him, he cannot accept the Twelve Step method of recovery, and he refuses to complete any of the tasks they set before him.

One evening, Leonard sits down with James and tells him a heart-wrenching story about his upbringing and how he landed in the clinic. Near the end of the story, Leonard breaks down and cries in front of James, and tells him to “hold on.” From this point onward, James has a deep respect for Leonard, and the notion of holding on resonates deeply with him. In the cafeteria, Lilly slides James a scrap of paper, which tells him to meet her in the clearing outside of the clinic. This is the start of the love affair between James and Lilly, a relationship they pursue though the clinic’s rules state that men and women patients cannot interact with each other. James and Lilly often meet for long periods of time, kissing, holding each other, and talking. The relationships with Lilly and Leonard are two of the truest that James has ever known.

James’s parents arrive at the clinic for the Family Program, despite his objections. Though seeing them is upsetting, James decides to participate. During a critical session, James finds out that he had an ear infection throughout his early childhood that made him scream and cry, which his parents left untreated. Also, he finds out that his grandfather had a drinking problem. James’s parents feel that maybe his grandfather’s addiction and the untreated ear infection had something to do with James’s addictions, but he refuses to accept this theory. As is his way in most areas of his life, James wants to go it alone and do things deeply and completely—this includes taking all responsibility for his condition. His addiction, he believes, is no illness. It is a weakness. It can only be overcome by taking full ownership. Once he comes to this conclusion, things begin to change for James.

James’s parents have to leave unexpectedly because James’s father has a pressing business engagement. Although their early departure upsets James, their good-byes are on good terms. Soon after, James finds out from a distraught Lilly that her grandmother is gravely ill and only has a short time to live. Lilly runs away from the clinic, and James literally runs off after her. Two clinic staff members, Hank and Lincoln, follow him in a van and offer assistance. She is eventually found in an abandoned building in the middle of a sexual act, and it is clear that she has been smoking crack. Though James sees crack and has a chance to use it, he chooses Lilly over the drugs. He brings her safely back to the clinic and is permitted to stay. Lilly is forced to start over again with detoxification and will have to pay for another term, something she cannot afford.

Continuing his quest to accept responsibility for his own life, James faces the criminal charges against him in Ohio. At first, he believes that he’ll have to be in jail for three years, but the sentence is mysteriously reduced to three months. James believes that his friend Leonard and his roommate Miles Davis helped reduce his sentence, but this fact is never confirmed. Leonard completes his program and prepares to leave the clinic. Before he does, he arranges for Lilly’s program to be paid for and asks James to be his son. The day before James leaves to begin his jail sentence, he confesses that a priest in Paris made unwanted sexual advances toward him, and that he beat the man seriously, possibly even killing him. This admission triggers a release in James, and he knows he is ready to leave. James’s brother and a friend pick him up at the clinic, and he immediately asks them to go to a bar. His brother and friend are stunned but give in to James’s request. At the bar James has Bob give him forty dollars and orders an entire pint glass full of whiskey. After looking at the glass and smelling the whiskey, James asks the bartender to pour it down the drain.