- Owen Meany's best friend, the narrator of the novel. The son of Tabby Wheelwright and Rev. Louis Merrill (though he does not know who his father is until the end of the novel), John is raised by the aristocratic Wheelwright family in Gravesend, New Hampshire. As a young man he is led to religious faith by the life of his best friend Owen Meany, and in 1987, he decides to write down Owen's story and to chronicle the awakening of his own belief in God. Though he has an active religious life, John is also extremely bitter and furiously angry about his experience, and frequently launches into lengthy diatribes against the Reagan administration. As a middle-aged man, he remains a virgin, "neutered," he says, by the things that have happened to him. In the novel, John serves both as a fixed perspective and as a contrast to the character of Owen Meany, a passive foil for Owen's charismatic dynamism.
- John's best friend, a dwarf with weirdly luminous skin and a high-pitched, nasal voice represented in the novel in all capital letters. Owen's father runs a granite quarry; some of Owen's eccentricities may be due to the inhalation of granite dust at an early age. Despite his tiny size, Owen is a powerful personality, often dominating situations and telling adults what to do even when he is a young child. Owen possesses a powerful and personal religious faith, believing himself to be God's instrument on Earth; he also believes that everything that happens is fated, and that his own dreams are prophecies of his future purpose in life. (As it turns out at the end of the novel, he is right.) When Owen and John are eleven, Owen accidentally kills John's mother when a foul ball he hits at a Little League game breaks her neck. Throughout the novel, Owen represents the relationship between the earthly and the spiritual, as well as the avocation of faith.
- John's youngest cousin (about a year older than he is), for whom John feels a bizarre, quasi-sexual attraction as a young man. Hester is extremely bitter about the inequitable treatment she receives from her parents, believing that they favor her brothers, and remains an angry, sexually and emotionally aggressive woman. By 1987, Hester has become a rock star, performing under the name "Hester the Molester." During their adolescence, Hester becomes romantically and possibly sexually involved with Owen Meany, and develops a passionate, fatalistic attachment to him. In the novel, Hester gives Irving an instrument for introducing the murky element of sexuality and gender relations into the lives of his boy-heroes. Like John, she remains deeply damaged by Owen's death for the rest of her life.
- John's mother, who keeps the identity of John's father a secret from him. Killed by a foul ball hit by Owen Meany in a 1953 Little League game, Tabby Wheelwright represents a kind of idealized vision of both motherhood and womanhood--as Owen, who has a terrible crush on her, says, she has "THE BEST BREASTS OF ALL THE MOTHERS."
- John's maternal grandmother, a domineering, aristocratic woman who loves her family very deeply. Descended from John Adams, and having married into the most prominent family in Gravesend, Mrs. Wheelwright is the matriarch of the town in her old age, and represents aristocracy and New England propriety throughout the novel. Mrs. Wheelwright maintains a manor at 80 Front Street in Gravesend, where John is largely raised and where many of the novel's most important events take place.
- John's stepfather, a young drama teacher who marries John's mother only a year before she dies. Dan remains in Gravesend on the academy faculty, and helps raise John as though he were his own son.
Reverend Louis Merrill
- The doubt-plagued Congregationalist minister in Gravesend, who often speaks to Owen about matters of religious faith. At the end of the book, John learns that the Rev. Merrill is his father.
Reverend Dudley Wiggin
- The brash, ridiculous Episcopalian rector in Gravesend, who puts on the ill-fated 1953 Christmas pageant in which Owen plays the baby Jesus. A former pilot, Rev. Wiggin prefers the most outlandish Bible verses. His wife Barb is a former stewardess.
- Dudley Wiggin's insufferable wife, a former stewardess. She intentionally gives Owen an erection just before the 1953 Christmas pageant, when he is dressed in swaddling clothes to play the baby Jesus.
- John's aunt, Tabitha Wheelwright's sister, and Harriet Wheelwright's daughter. Martha is neither as pretty as Tabby nor as talented a singer, and John suspects that she is slightly jealous of her. Martha is married to Alfred Eastman, and lives in Sawyer Depot with her husband and their three children.
- John's uncle by marriage, a rugged lumber baron who lives in Sawyer Depot.
- John's oldest cousin, Hester and Simon's brother. Wild and unruly as a youth, Noah attends Gravesend Academy and a college on the West Coast.
- John's second-oldest cousin, Noah and Hester's brother. Even wilder than Noah as a youth, Simon follows his brother to Gravesend Academy and a college on the West Coast.
- John's neighbor, who lives next to 80 Front Street and who loves to act in Dan Needham's Gravesend Players productions. Mr. Fish has a dog named Sagamore, which is killed by a diaper truck when John and Owen are children.
- The headmaster at Gravesend Academy, who is responsible for Owen's expulsion shortly before graduation. Mr. White loses his job as a result of the incident.
- Mrs. Wheelwright's maid, who loses a leg to cancer. She spends the rest of her life in a wheelchair at 80 Front Street, gradually becoming more and more like Mrs. Wheelwright's double.
- The Little League coach who orders Owen to bat for John in their final game. When he goes to the plate, Owen hits the foul ball that kills John's mother. Mr. Chickering blames himself, and sobs at the funeral.
- The fat, self-conscious boy who is chosen to play the Announcing Angel in the Christmas pageant.
Mary Beth Baird
- The over-zealous Mary in the Christmas pageant, who later speaks to John at Owen's funeral.
- The boy who kills Owen Meany. A hulking, sadistic fifteen-year-old from a trashy family in Phoenix. Dick lives for the day when he will be old enough to travel to Vietnam; he dreams of slaughtering the Viet Cong. Owen is assigned to return the body of Dick's dead brother. When Dick sees Owen escorting a group of Vietnamese orphans into a men's room, he throws a grenade into the room. Owen is killed in the act of saving the children's lives.
- The maid hired to replace Lydia at 80 Front Street.
- A young, superstitious maid hired to care for Lydia after she loses her leg. Germaine is reading to Lydia when she dies.
- The Episcopalian Sunday school teacher who always blames Owen when the other students lift him up and pass him around. Mrs. Walker also acts in Dan's Gravesend Players productions.
- A young faculty wife at Gravesend Academy, a legendary sex symbol to academy boys. One Christmas holiday, shortly after the Brinker-Smiths have twins, John and Owen discover that the couple is engaged on a campaign to have sex in every dorm room in the building.
- Tabby Wheelwright's Boston-based singing teacher, who tells Owen and John about Tabby's career as "The Lady in Red," a singer in a supper club called The Orange Grove.
- The over-sophisticated, cowardly Gravesend Academy boy who reveals to the police that Owen has been making fake IDs for academy students, giving Mr. White an excuse to expel Owen.
- Larry Lish's mother, a wealthy divorcee who tells Owen about John F. Kennedy's affair with Marilyn Monroe.
- Owen's father, a lumbering, simple man who runs a granite business. When Owen is eleven, his father and mother tell him that he was a virgin birth.
- Owen's mother, a melancholy woman who spends all her time indoors and almost never speaks.
- Owen's military contact in Phoenix, who kills Dick Jarvits after Dick kills Owen.