A Prayer for Owen Meany can be really complex at times. All of the historical references (like the Vietnam War, the assassination of JFK, and the Iran-Contra affair) and all of the pop culture and literary references can leave you scratching your head. Still, you'll find pretty quickly that you don't need to have the best handle on these tidbits in order to understand what's actually happening in the novel. For instance, you don't really need to know what Ronald Reagan specifically was up to during the Iran-Contra affair to understand that John is really critical of the United States; you don't really need to know everything about the Kennedys to understand how shocked Owen and John are when JFK is assassinated.
If anything, the most complex aspect of this novel is that there are so many tiny details and clues that keep reappearing and popping up. Everything little thing that happens seems to be a piece of a larger puzzle that isn't completed until the very end. It seems like everything happens for a reason (a sentiment that we think Owen and John would agree with). That said, A Prayer for Owen Meany is such a funny and engaging novel with such humorously memorable moments that you'll probably find yourself absorbing most of what you read and wanting to figure out what everything means.