Alsace Travel Quandary

I'm not sure there's a really efficient way to get from Frankfurt airport to Kayserberg, it would involve either a train/bus combo from Frankfurt or a short flight to Basel, then train & bus. I think I might just rent a car at the Frankfurt airport and drive to Kayserberg, then when you're done with the car drop it somewhere across the border in Germany (to avoid drop off charges) and take the train to the BO. You could check to see if you could drop the car at the Basel train station without a drop off charge but I don't know about that.

The train from Frankfurt airport to Colmar takes about 3.5 hours, probably more efficient than flying to Basel. Depends on the time of your arrival and how many options there are for trains so research at Bahn.de but do not buy until you are confident you will make the train, i.e., usually wait until landing..

Rent a car in Colmar and return it there. Colmar to Interlaken, gateway to the Lauterbrunnen Valley where many of us recommend spending time, in another 3 hour train trip with a change at Basel. Research at SBB.ch and buy there as well. Buying in advance on a inter-country ticket there is usually a savings but the tickets are non-refundable. You may want to explore a Berner Oberland Regional Pass for your time.

I agree with Laurel. Rent and return the car in Colmar. Frankfurt airport to Colmar and Colmar to Berner Oberland are easy by train.
Berner Oberland back to Frankfurt airport is also easy by train.
Note I am saying "Frankfurt airport" (station name: Frankfurt(M)Flughafen), this is the station at the airport terminal, a different station than Frankfurt city centre.

Look up train times on either the DB (German Railways) website: https://www.bahn.com/en/view/index.shtml
or SBB (Swiss Railways): https://www.sbb.ch/en
Both these sites will give train times for all your trips, however they won't sell you tickets for trips wholly outside their country. SBB won't sell you Frankfurt airport-->Colmar (DB will), DB won't sell Colmar-->Berner Oberland (DB only). Both will sell you Berner Oberland-->Frankfurt airport.

As far as getting from Frankfurt to Colmar, I see a few train options at about $140 for the two of us - which seems a little steep. I just found out about Flixbus, any experience with that? It's about $35 for the two of us to Colmar and doesn't have 3 changing connections like the train. Then I could rent the car in Colmar like you said!

I took a Flixbus from Frankfurt to Trier and it was an okay experience. Under the right circumstances I would do it again. One of the advantages to the train is that you can get up and walk around. After an international flight that is something to consider.

Non-stop Lufthansa Express Bus runs b/w Frankfurt Airport terminal and Strasbourg Gare (train station). Very reliable and train-strike proof. I've been taking this bus for more than a decade. https://www.lufthansa.com/de/en/lufthansa-express-bus-stops. Then TER to Colmar + bus to Kaysersberg. FYI -- No direct ICE/TGV train from Frankfurt Airport to Strasbourg. Need minimum 1 connection.

If you take the Lufthansa express bus you could pick up your rental car in Strasbourg and drive to Kayserberg. That would be approximately an hour drive. If you don't want to drive that far on arrival day you could train from Strasbourg to Colmar (30 minutes) and pick up your car in Colmar. Kayserberg is approximately 20 minutes from Colmar. That would minimize your driving.

I would go to Strasbourg from Frankfurt - either Lufthansa bus from the airport or the train with a transfer at Frankfurt Hbf. You are more likely to get a better deal on a rental car in Strasbourg since there are several companies there, but only one in Colmar. It's about an hour's drive to Kayserberg.

Do check for drop-off charges from Germany to Switzerland. Several years ago I looked into it, and there weren't any. I believe you can also drop a car in Geneva on the French side (maybe at the aiport?).

Consider Strasbourg as an option. It seems to me it would be at least somewhat quicker than getting to Colmar. You can rent a car there and drive through Alsace.

Colmar is closer to Keysersberg but the area isn't large. It may be faster renting a car and driving from Strasbourg than waiting for a train connection to Colmar.

Other options for renting, only if you plan to return the car in Germany, would be Heidelberg or Freiburg.

Since you're flying in and out of Frankfurt why don't you just rent a car for the entire trip? We were in the Colmar/Kaysersberg area back in December and had no problems driving/parking. Friends of ours flew into Frankfurt and drove down to meet us - no problems. Two years ago we visited the BO and also had a car - no problems then either. Driving will open up your trip to more places/flexibility than if you're stuck relying only on trains and buses.