The novel deals with serious spiritual issues, such as the importance of faith, matters of social justice, and the concept of fate, in the context of an outlandish narrative. Throughout the novel, John and Owen both offer criticisms of organized religion and religious hypocrisy. However, the spiritual dimension is repeatedly emphasized by Owen's foretelling of his own impending death. He is quite certain that he will die because he is an "instrument of God" and thus will serve some good and important purpose. He also believes that he knows the date of his death and that a heroic act on his part will kill him but also save some children. He is a bit unclear, however, about where and how this act will occur.
The narrative is constructed as the interweaving of three different stories of past John, present John, and Owen's life. There is the historical retelling of John's and Owen's childhood; the story of their (and particularly Owen's) adult lives; and the story of John's life after Owen's death. The three streams are brought together at the dénouement — the death of Owen. Owen had always predicted both the manner and the importance of his own death.
The familiar Irving setting (based on his own biography) of a New England private school relates the novel to the frameworks of his other works. However, other familiar Irving themes and settings (e.g., prostitutes, wrestling, and Vienna) are missing, or mentioned only briefly.
Young Johnny Wheelwright is skeptical of Owen Meany's unquestioned belief in the purpose of all things. He has certain reasons: namely, his mother's premature death (as the result of the impact of a baseball hit by Owen), and his mother's failure ever to disclose his father's identity. John is depicted as being spiritually apathetic as a youth, but the conclusion brings these spiritual pieces of the story together. Since the novel is written retrospectively, much of the novel takes the tone of John's new-found wisdom.
John occasionally withdraws from the past to offer criticisms of the Vietnam War and the Iran-Contra Affair.
The setting is based on Phillips Exeter Academy, in Exeter, New Hampshire. A real-life John Wheelwright was the founder of the town of Exeter in 1638.