Never Let Me Go is told from the perspective of Kathy, a clone, as she looks back on her childhood and youth, especially on her friendship with classmates Tommy and Ruth. Kathy and the other clones she grew up with are kept separate from the normal society, destined to first become carers for other clones, and then donors of vital organs for the rest of the population. Even though she knows her ultimate destiny, Kathy struggles with friendship, love, and the meaning of her life.
The story begins with Kathy, a carer, talking about looking after donors. She has been a carer for almost twelve years at the time of narration, and she often reminisces about her time spent at Hailsham, a fictional boarding school in England, where the teachers are known as guardians. Along with classes, they often emphasize the importance of keeping healthy to their students—smoking is considered to be taboo, almost on the level of a crime, and working in the vegetable garden is compulsory. The curriculum appears to be like that of any other school, but there is great encouragement for the students to produce art. The art is then displayed in an exhibition, and the best artwork is chosen by a woman known to the students as Madame. The students speculate that she keeps their work in a gallery.
The story revolves around three Hailsham students: Kathy, and two others, Ruth and Tommy, who develop a close but complicated friendship. Kathy develops a fondness for Tommy, looking after him when he is bullied and having private talks with him. However, Ruth and Tommy begin a romantic relationship during their time at the school that continues when they leave.
In an isolated incident, Miss Lucy, one of the guardians, talks to the students about their goals and their true purpose: to provide organs to others, a cycle of donations that will consume their lives. This results in Miss Lucy's removal from the school, though it causes only subtle disturbance in the students, who were raised with the notion.
At age 16, Ruth, Tommy and Kathy move to the Cottages, a poorly maintained residential complex where they begin contact with the outside world. Ruth and Tommy continue their relationship, and Kathy has some sexual, but shallow, relationships with other men. Kathy is concerned that her sex drive is abnormal, and Ruth deliberately encourages her to feel this way when she confides in her.
Two older housemates, who had not been at Hailsham, tell Ruth that they have seen a "possible" for Ruth, an older woman who resembles Ruth and thus could be the woman from whom she was cloned. As a result, the five of them go on a trip to see her, but the two older students first want to discuss a rumour they have heard that a couple can have their donations deferred if they can show that they are truly in love. They believe that this privilege is for Hailsham students only and so wrongly expect that the others will know how to apply for it. They then find the possible, but the resemblance to Ruth is only superficial.
During the trip, Kathy and Tommy separate from the others and look for a copy of a tape that Kathy had lost when at Hailsham. Tommy's recollection of the tape and desire to find it for her make clear the depth of his feelings for Kathy. They find the tape, and then Tommy shares with Kathy a theory that the reason Madame collected their art was to determine which couples were truly in love, citing a teacher who had said that their art revealed their souls. After the trip, Kathy and Tommy do not tell Ruth of the found tape, nor of Tommy's theory about the deferral.
When Ruth finds out about the tape and Tommy's theory, she takes an opportunity to drive a wedge between Tommy and Kathy. Shortly afterwards she tells Kathy that even if Ruth and Tommy were to split up, Tommy would never enter into a relationship with Kathy because of her sexual history. A few weeks later, Kathy applies to become a carer, meaning that she will not see Ruth or Tommy for many years.
Ten years pass without Kathy seeing Ruth or Tommy, during which time Hailsham closes. Ruth's first donation goes badly and her health deteriorates. Kathy becomes Ruth's carer, and both are aware that Ruth's next donation will probably be her last. Ruth suggests that she and Kathy take a trip and bring Tommy with them. During the trip, Ruth expresses regret for keeping Kathy and Tommy apart. Attempting to make amends, Ruth hands them Madame's address, urging them to seek a deferral. Shortly afterwards, Ruth makes her second donation and completes.
Kathy becomes Tommy's carer and they begin a romantic relationship. Encouraged by Ruth's last wishes, they go to Madame's house to see if they can defer Tommy's fourth donation, bringing Tommy's artwork with him to support their claim that they are truly in love. They find Madame at her house, and also encounter Miss Emily, their former headmistress, who lives with her. They reveal that Hailsham was an experiment to give clones humane treatment, in contrast to other institutions. The gallery was used to help get funding, by conveying to the outside world that clones are in fact real humans. They are not able to give deferrals, and never had that power.
Tommy knows that his next donation will be his last, and this happens a few months after they visit Madame. The novel ends with Kathy alone, knowing that she will start her donations in a few months.