Using alternating first-person perspectives, the novel tells the stories of Henry DeTamble (born 1963), a librarian at the Newberry Library in Chicago, and his wife, Clare Anne Abshire (born 1971), an artist who makes paper sculptures. Henry has a rare genetic disorder, which comes to be known as Chrono-Impairment, that causes him to involuntarily travel through time. When 20-year-old Clare meets 28-year-old Henry at the Newberry Library in 1991 at the opening of the novel, he has never seen her before, although she has known him most of her life.
Henry begins time traveling at the age of five, jumping forward and backward relative to his own timeline. When he leaves, where he goes, or how long his trips will last are all beyond his control. His destinations are tied to his subconscious—he most often travels to places and times related to his own history. Certain stimuli such as stress can trigger Henry's time traveling; he often goes jogging to keep calm and remain in the present. He also searches out pharmaceuticals in the future that may be able to help control his time traveling. He also seeks the advice of a geneticist, Dr. Kendrick. Henry cannot take anything with him into the future or the past; he always arrives naked and then struggles to find clothing, shelter, and food. He amasses a number of survival skills including lock-picking, self-defense, and pickpocketing. Much of this he learns from older versions of himself.
"It's hard being left behind. I wait for Henry, not knowing where he is, wondering if he's okay. It's hard to be the one who stays."
Once their timelines converge "naturally" at the library—their first meeting in his chronology—Henry starts to travel to Clare's childhood and adolescence in South Haven, Michigan, beginning in 1977 when she is six years old. On one of his early visits (from her perspective), Henry gives her a list of the dates he will appear and she writes them in adiary so she will remember to provide him with clothes and food when he arrives. During another visit, he inadvertently reveals that they will be married in the future. Over time they develop a close relationship. At one point, Henry helps Clare frighten and humiliate a boy who abused her. Clare islast visited in her youth by Henry in 1989, on her eighteenth birthday, during which they make love for the first time. They are then separated for two years until their meeting at the library.
Clare and Henry marry, but Clare has trouble bringing a pregnancy to term because of the genetic anomaly Henry may presumably be passing on to the fetus. After six miscarriages, Henry wishes to save Clare further pain and has a vasectomy. However a version of Henry from the past visits Clare one night and they make love; she subsequently gives birth to a daughter, Alba. Alba is diagnosed with Chrono-Impairment as well but, unlike Henry, she has some control over her destinations when she time travels. Before she is born, Henry travels to the future and meets his ten-year-old daughter on a school field trip and learns that he dies when she is five years old.
When he is 43, during what is to be his last year of life, Henry time travels to a Chicago parking garage on a frigid winter night where he is unable to find shelter. As a result of the hypothermia and frostbite he suffers, his feet are amputated when he returns to the present. Henry and Clare both know that without the ability to escape when he time travels, Henry will certainly die within his next few jumps. On New Year's Eve 2006 Henry time travels into the middle of the Michigan woods in 1984 and is accidentally shot by Clare's brother, a scene foreshadowed earlier in the novel. Henry returns to the present and dies in Clare's arms.
Clare is devastated by Henry's death. She later finds a letter from Henry asking her to "stop waiting" for him, but which describes a moment in her future when she will see him again. The last scene in the book takes place when Clare is 82 years old and Henry is 43. She is waiting for Henry, as she has done most of her life.