Hi Scott -
I like the way you are looking at this - what's unique about the US? A lot of those cities have been mentioned. (Most recently by Rich, as I am just noticing.) I will put in a plug for the following:
Chicago. In fact, if you are serious train fans, then one good option may be to fly into Chicago to start your trip, then take the overnight train towards NYC, which drops you in Buffalo (for Niagara Falls) at 9am. (You could even take this route from South Bend, Indiana/Notre Dame, in case you wanted to see a football game there.) That same train the next day can bring you from Buffalo to Boston, or you can take that side jog from Bflo to Toronto. It will be after peak foliage season, fwiw, but still a good countryside trip.
If you are anywhere near Lexington, North Carolina, there's a great small town for you. Mainly because it's the pork BBQ capital of the world. Eat here:
http://www.hollyeats.com/Lexington.htmWarning: If your good lady is a furniture/antique devotee, please forget immediately that I ever said anything at all about western North Carolina.
Or maybe that's the trade: she can go drool over furniture, and you can eat pork shoulder, hush puppies, red vinegar slaw, and cobbler for 6 hours. Come to think of it, that would work. (If you go from Wash DC / Williamsburg VA to Atlanta, it's right on your way.)
College football. If you wanted to combine it with some beach time, Georgia plays Florida in Jacksonville, FL on Oct 31st - that might be a bit early for your schedule, but it's a huge game. Otherwise, Auburn is right on the way from Atlanta to New Orleans. And Florida usually plays in Gainesville, which is not far from Disneyworld - if you do decide on Orlando.
New Orleans (a couple days is good). Dinner here
http://www.courtoftwosisters.com/ if the weather is nice out - you'll get brownie points for this.
San Antonio is a great city for a couple days, but honestly it's not really close to any other must-see kind of place. (And I live in Houston.) But see below for flights.
Grand Canyon. If an American spends any time in Oz, he should go see Uluru, right? Same idea.
Las Vegas. Go once, just to see the spectacle. Once is plenty enough for many (most?), but do go once. Plus if you drive to Vegas from the GC, you'll spend much of that drive on Route 66 (now Interstate 40), if that has any appeal for you. You also go right over the Hoover Dam.
So to sum up, Chicago plus Chris Garrett's East plus San Antonio plus Cabell Ackerly's West (Moab is a cool idea), I guess. And Charleston or Savannah is plenty, I don't think you need both.
This could save you lots of driving in the east. In fact, you probably wouldn't need a car until you left DC. Drive down to Georgia, maybe Florida. Southwest Airlines does have non-stops from Orlando to N.O., easy connections from N.O. to San Antonio, and non-stops from S.A. to Denver. Your longest drive there would be getting from the Denver airport to Denver itself! But that way you wouldn't already be sick of the road before racking up all those miles out west.
I wouldn't put Memphis ahead of San Antonio, I don't think, and definitely not before New Orleans or Chicago. And while I think Seattle is nice enough, I don't consider it a must-see except perhaps as a logical stop after a possible Bandon pilgrimage.