Mitch Albom, the book's narrator, recalls his graduation from Brandeis University in the spring of 1979. After he has received his diploma, Mitch approaches his favorite professor, Morrie Schwartz, and presents him with a monogrammed briefcase. While at Brandeis, Mitch takes almost all of the sociology courses Morrie had teaches. He promises Morrie, who is crying, that he will keep in touch, though he does not fulfill his promise. Years after Mitch's graduation from Brandeis, Morrie is forced to forfeit dancing, his favorite hobby, because he has been diagnosed with ALS, a debilitating disease that leaves his "soul, perfectly awake, imprisoned inside a limp husk" of a body. Morrie's wife, Charlotte, cares for Morrie, though at his insistence, keeps her job as a professor at M.I.T.
Sixteen years after his graduation from Brandeis, Mitch is feeling frustrated with the life he has chosen to live. After his uncle dies of pancreatic cancer, Mitch abandons his failing career as a musician to become a well-paid journalist for a Detroit newspaper. Mitch promises his wife Janine that they will have children eventually, though he spends all of his time at work, away on reporting assignments. One night, Mitch is flipping the channels on his television and recognizes Morrie's voice. Morrie is being featured on the television program "Nightline" in the first of three interviews with Ted Koppel, whom he quickly befriends. Before consenting to be interviewed, Morrie surprises and softens the famed newscaster when he asks Koppel what is "close to his heart." Mitch is stunned to see his former professor on television.
Following Morrie's television appearance, Mitch contacts his beloved professor and travels from his home in Detroit to Morrie's home in West Newton, Massachusetts to visit with him. When Mitch drives up to Morrie's house, he delays greeting his professor because he is speaking on the phone with his producer, a decision he later regrets.
Shortly after his reunion with Morrie, Mitch works himself nearly to death reporting on the Wimbledon tennis tournament in London. There, he spends much time thinking about Morrie and forfeits reading the tabloids, as he now seeks more meaning in his life and knows that he will not gain this meaning from reading about celebrities and gossip. He is knocked over by a swarm of reporters chasing celebrities Andre Agassi and Brooke Shields, and it is then that Mitch realizes he is chasing after the wrong thing. When he returns to his home in Detroit, Mitch learns that the article he has worked so hard to write will not even be published, as the union he belongs to is striking against the newspaper he works for. Once more, Mitch travels to Boston to visit Morrie.
Following their first Tuesday together, Mitch returns regularly every Tuesday to listen to Morrie's lessons on "The Meaning of Life." Each week, Mitch brings Morrie food to eat, though as Morrie's condition worsens he is no longer able to enjoy solid food. In his first of three interviews with Koppel for "Nightline," Morrie admits that the thing he dreads most about his worsening condition is that someday, he will not be able to wipe himself after using the bathroom. Eventually, this fear comes true.
Interspersed throughout Mitch's visits to Morrie are flashbacks to their days together at Brandeis. Mitch describes himself as a student who had acted tough, but had sought the tenderness he recognized in Morrie. At Brandeis, Mitch and Morrie shared a relationship more like that between father and son than teacher and student. Soon before Morrie's death, when his condition has deteriorated so much that he can no longer breathe or move on his own, he confides that if he could have another son, he would choose Mitch.
In his childhood, Morrie had been very poor. His father, Charlie had been cold and dispassionate, and had neglected to provide for Morrie and his younger brother emotionally and financially. At the age of eight, Morrie must read the telegram that brings news of his mother's death, as he is the only one in his family who can read English. Charlie marries Eva, a kind woman who gives Morrie and his brother the love and affection they need. Eva also instills in Morrie his love of books and his desire for education. However, Charlie insists that Morrie keep his mother's death a secret, as he wants Morrie's younger brother to believe that Eva is his biological mother. This demand to keep his mother's death a secret proves a terrible emotional burden for young Morrie; he keeps the telegram all of his life as proof that his mother had existed. Because he was starved of love and affection during his childhood, Morrie seeks it out in his old age from his family and friends. Now that he is nearing his death, Morrie says that he has reverted to a figurative infancy, and tries in earnest "enjoy being a baby again." He and Mitch often hold hands throughout their sessions together.
In his lessons, Morrie advises Mitch to reject the popular culture in favor of creating his own. The individualistic culture Morrie encourages Mitch to create for himself is a culture founded on love, acceptance, and human goodness, a culture that upholds a set of ethical values unlike the mores that popular culture endorses. Popular culture, Morrie says, is founded on greed, selfishness, and superficiality, which he urges Mitch to overcome. Morrie also stresses that he and Mitch must accept death and aging, as both are inevitable.
On one Tuesday, Janine travels with Mitch to visit Morrie. Janine is a professional singer, and Morrie asks her to sing for him. Though she does not usually sing upon request, Janine concedes, and her voice moves Morrie to tears. Morrie cries freely and often, and continually encourages Mitch to do so also. As Morrie's condition deteriorates, so does that of the pink hibiscus plant that sits on the window ledge in his study. Mitch becomes increasingly aware of the evil in media, as it drenches the country with stories of murder and hatred. One such story is the murder trial of O.J. Simpson, the verdict of which causes major racial division between whites and blacks.
Mitch tape records his discussions with Morrie so that he may compile notes with which to write a book, Tuesdays With Morrie, a project which he and Morrie refer to as their "last thesis together." Morrie continually tells Mitch that he wants to share his stories with the world, a the book will allow him to do just that.
Meanwhile, at Morrie's insistence, Mitch attempts to restore his relationship with his brother Peter who lives in Spain. For many years, Peter has refused his family's help in battling pancreatic cancer and insists on seeking treatment alone. Mitch calls Peter and leaves numerous phone messages, though the only reply he receives from his brother is a curt message in which Peter insists he is fine, and reminds Mitch that he does not want to talk about his illness. Morrie prophetizes that Mitch will once more become close with his brother, a prophecy which, after Morrie's death, is realized. At Morrie's funeral, Mitch recalls his promise to continue his conversations with his professor and conducts a silent dialogue with Morrie in his head. Mitch had expected such a dialogue to feel awkward, however this communication feels far more natural than he had ever expected.