The weather in northern Spain (now in Basque country) has deteriorated since my June 14 post. Cooler and wetter. Keep this in mind since you are planning a fall trip.
I think David's suggestion of one night in Bilbao would be OK for a lot of people. Many apparently day-trip in from San Sebastian, but I think that's a shame, because Bilbao is very attractive. I'd at least want to walk through the old quarter (Casco Viejo) as well as see the Guggenheim. The 19th century Ensanche area is very nice also. There's nothing about the city that I would consider "gritty" at this point.
I liked the 75-minute free English tour I took at the Guggenheim. It was at 1215 or 1230, but it's prudent to stop at the info desk as aoon as you arrive to get the requisite sticker. The tour covered the history of the museum and the ground-floor exhibits (Serra sculptures, outdoor sculptures, and the temporary Warhol exhibit). Afterward, I wandered slowly through the second floor, spending about 75 minutes there as well. There's additional sculpture to see along the river if you hit decent weather.
I believe the Bellas Artes Museum in Bilbao is also very worthwhile, but it is unfortunately closed at the moment due to a strike by employees of the company that provides visitor services. No info on how long the strike may last. I went to the Basque Museum in the Casco Viejo and consider it skippable; however, I confess that that's my reaction to just about every ethnographic museum I've seen. I suspect that the hour-long boat trip on the river is very nice, but I didn't have time to do that while the weather was cooperating.
For others visiting this area who may not have a car, I agree with Rick that the slow euskotren between Bilbao and San Sebastian takes a very attractive and interesting route. Two and a half hours, with a one-way fare of 6.90 euros.
Edited to add: I haven't driven in Europe, but there's nothing about the northrern part of Spain (excluding Barcelona proper) that makes driving look difficult. I'm mostly using buses, which have been pretty much on time and comfortable (there's normally even toilet pepper in the bus station restroms!). Service between your cities is generally reasonably frequent, but rarely more than once an hour, at best, so there is some time wasted due to the schedules. Laguardia seems to be the most isolated spot on your list. You can reach it from Vitoria-Gasteiz by taking the Logrono bus; Laguardia is one of the last stops before Logono. I think that trip isn't much more than an hour. I'm nearly certain that the route from San Sebastian would be via Pamplona and Logrono and would take longer, but I haven't rsearched the details of that route. It's quite possible that the shortest total route covering the three Basque cities and Laguardia would be Bilbao - Vitoria-Gasteiz - Laguardia - San Sebastian or the reverse.
