The novel is told through the eyes of an older, much more matured John Wheelwright who elaborates on the stuffs happening surrounding his close friendship with Owen Meany during the 1950s and 1960s, which he says is responsible for his belief in God. Owen is very short and his voicebox is fixed so that he sounds as if he is always screaming. Owen, being the shortest one amongst his friends makes him the butt of many jokes and pranks, though his peers do not generally dislike him. Children and adults alike seem drawn to and almost protective of Owen. Owen is also the recipient of many special privileges, such as getting to play the baby Jesus in a Christmas pageant because he is the only actor who can fit in the crib and not cry.

The novel deals with several spiritual issues, such as the importance of faith, social justice, and fate. John and Owen both offer criticisms of some aspects of organized religion and the hypocrisy of some religious people throughout the novel. The spiritual dimension is also brought up by Owen's repeated foretelling of his own death. He is quite certain that he will die because he is an "instrument of God", thus serving some good purpose. He even 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 it will happen.

Young John is skeptical of Owen's unquestioned belief in the purpose of all things for several 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 influenced 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 newfound wisdom.