Blackforest or Rhine Valley? Ome night and a day

I've done both - came in from Boppard on a direct RE and from Karlsruhe on an ICE - but both for a flight in the early afternoon.

It might partially depend on the airline you are flying. The RE from the Rhein gets you into the Regionalbf at 8:35. If you are flying Lufthansa or United,which use Terminal 1, 2½ should be enough time (it always has been for me). For other US airlines that use Terminal 2, I'm not so sure. And the towns are in line, so even from Boppard, you can leave after 7 AM.

On the other hand, coming in from the Rhein valley main line, the ICE arrives at 9:06, too late for comfort, particularly since you will arrive at the farther out Fernbahnhof, or at 9:06, which means leaving most Rhein stations before 7 AM. And from anywhere in the Black Forest, getting to the Rhein main line will take more times.

So, I think the Rhein gorge would be the better place for the last night.

"...where to make our last stop before spending the night near the Frankfurt airport to catch a 11 am flight home..."

So just part of one day, then a night... The Rhine Valley would work. If you want to be just 25 minutes from FRA (by train) you can stay in Mainz. Direct trains leave Mainz starting at 4 am and head straight to the airport terminal. (If you are driving, drop the car in Mainz the night before you leave.)

Planning your last sightseeing day: At a minimum, get yourselves to Bingen, where you can board a river cruise boat to St. Goar and tour Rheinfels Castle there. Return to Bingen (if you left the car there) by train, stopping off for a visit in either in Bacharach or Oberwesel if you have the time. (If you are getting around by train, then you can return straight to Mainz without stopping over in Bingen.)

Scene near Bingen
Scene from riverfront in St. Goar
Rheinfels Castle

There are too many ways (traffic jams, wrong turn) to get delayed if traveling by car. I have more trust in the trains to get you there on time.

I agree with Russ and would spend the last night in Mainz, then take an early morning train straight to the airport.

For other US airlines that use Terminal 2, I'm not so sure.

The airport info flyer suggests to add 25min for the bus transfer from the train to terminal 2. In peak times that might be a minimum. Sometimes buses are full and waiting for the next one adds 5-10 min easily.

The bus only takes 5-6 minutes from T1 to T2, but there can be as much as 15 minutes between buses (20 min total). However, you don't have to take the bus. There is also the SkyLine, a people mover that goes from the top of T1 to the top of T2. Even going up and down escalators to get to and from it, it can't take any longer than the worst case bus with waiting times.

As for spending the last night in Mainz, there are three hotels (Hammer, Königshof, and Schottenhof) right across the Bahnhofsplatz from the station. It's just a short walk from any of them to the S-Bahn to the airport.