I'd echo
@noharleyyet's sentiment that this is entirely subjective, but if I were to try and make a case under this premise, I would say Gatsby.
Shocking as it may seem for someone who did an MA in English and specialized in Hemingway... but if I am trying to think of a book that continues to capture the American experience in as many of it's facets possible, Gatsby seems the most applicable to the op's premise.
From commentary on the trappings of capitalism, old money, new money, pining for the unattainable, remaking oneself, to the corrupt, hedonistic aftermath of the world post the Great War during prohibition and the philosophical shift that happened in the modernist era.... it sure checks a lot of boxes.
Heck, Gatsby gets his money from a yachtsman in the midwest, who got his money from the Montana copper mines, so even some of that pioneer/frontierism/manifest destiny narrative romanticized by Lonesome Dove makes an appearance.
Grapes of Wrath comes in close second. If Gatsby is the Pride before the Fall, then Grapes of Wrath is the Fall. In terms of American Mythmaking, Grapes of Wrath has become one of the most retold stories in America (lots of family road-trip stories out there, some funny, some serious).
Though really, this is of course Westernized logic throughout, and the Great American Novel is probably something more along the lines of Fools Crow by James Welch, depicting the atrocities of manifest destiny through the eyes of those who were victim to it and here before any of us.
Pat McManus didn't write any novels to my knowledge, but his best collection of short stories is his first: A Fine and Pleasant Misery. His work started to become a little repetitive in his later years.
Or maybe the Great American Novel is Twilight. Mormon-coded love triangle teen fiction about vampires that made a massive amount of money and movie royalties, and inspired Fifty Shades of Gray. What's more American than that?
My 2 cents. Worth less than that I'm sure.
