It’s like Lord of the Rings. Published in separate books, but actually one novel.
And my copy is bound together in one novel, called The Book of the New Sun.
Willa Cather’s O Pioneers!
I first read it in college for an American Lit class. It spoke to me and I have reread it often over the intervening years.
By cutting off the first two words of my parenthetical phrase, you changed its meaning. :dubious:
Probably obvious, my vote goes to All the King’s Men, by Robert Penn Warren
The Grapes of Wrath. I loved everything about it.
I have to go with Moby Dick myself, as the novel I will pick up and ready again at any time.
I didn’t think, at the time, that I was doing so, but now I see that I mis-parsed your comment. I read it as “and choosing, despite the OP’s admonition to stick to the American-themed”; when what you meant was “and choosing, despite the OP’s admonition, to stick to the American-themed.” My apologies.
Bukowski’s novels are all good reads - Factotum, Post Office & Ham on Rye.
It’s easier for me to list my twenty favorite science fiction novels and my twenty favorite fantasy novels than to list my one favorite of each. I don’t pretend to know other genres as well, so I won’t even try to list a favorite among them. A couple of science fiction and fantasy novels that haven’t been given yet that I like are these:
Walter Miller A Canticle for Leibowitz
Peter Beagle The Last Unicorn
Gone with the Wind
Yeah I know. Shut-up.
Sinclair Lewis’s Babbitt. It always explained so much of America to me.
I should have used commas. 
Moby Dick. Close the thread.
Yeah, Moby-Dick also counts as a favorite.
Call me closed.
Upon reflection, I am torn between Lord of Light and Something Wicked This Way Comes.
Look Homeward, Angel.
Same here. I’ve read it at least half a dozen times since 1970.
My very close second favorite: One Flew Over The Cuckoo’s Nest.
The Bluest Eye. I’m glad this thread specified American novels, because it’s nose-and-nose with Howard’s End, a British novel, for being my favorite of all time.
ETA: reading back through the thread, I see Bukowski mentioned. I do think Post Office is a freaking fabulous novel (with the best first chapter ever), and rates among my top ten, as does Moby Dick. But The Bluest Eye beats them all.
Don’t miss Memoir from Antproof Case. It’s completely absorbing and very funny. I should have put it on my list.
Another vote for A Prayer for Owen Meany. If I couldn’t pick that one, I’d go with another John Irving. I just love his characters.