Bilbao is a 'Competitive' airline market city, so you should be able to get good fares to/from there and Madrid, Barcelona or even Frankfurt.
Don't just do the Guggenheim! Visit the Casco Viejo; visit la Begonia! take a little time to sample the Basque cuisine.
You don't tell us when you are going. If it's around 15 Sep that's el dia de Cantabria. Santander is the Capital of Cantabria and it is a major holiday there. It would probably take you an hour Bilbao-Santander (the bus takes 1.25 hours). Allow another hour for Santillana del mar. San Sebastian to/from Bilbao would be just a little more than an hour's drive.
For such a short stay, I would base myself in Bilbao (I stayed at the Hotel Conde Duque, on the rio Nervion, about 1km from the Guggenheim).
Bilbao, San Sebastian & Santillana del mar is a 'tall order' for 3-days. IMHO you should cut out the western 'leg' of your trip (unless you want to cut the number of days in Barcelona) and fly Madrid-Bilbao and Bilbao-Barcelona.