Northern Spain Visit ~ Suggestions

Almost in the border with the French Basque Country, you can´t miss Hondarribia, beautiful town. Then, to the west, Getaria is a must for the town and its "txakoli" wineries (and if you can have lunch or dinner there, it´s a plus for the best seafood), Zumaia and the amazing "flysch", then Lekeitio, Ea, Elantxobe, Plentzia, Getxo and then Bilbao, that deserves at least one day or two. On the way to Santander, Castro Urdiales, and maybe Santillana del Mar (but very touristy). Inland, Gernika deserves a visit, as well as (if you have time) a detour to Rioja wine region (Rioja Alta and Rioja Alavesa mainly), with a visit to the wonderful family owned wineries using cellars over 500 years old.

Plenty to see and do. Mike covered the north coast in that area very well. It’s only a couple hours drive between San Sebastián and Santander so you’ll have plenty of time to sightsee. From Madrid, you didn’t state how many days you plan to take to get to San Sebastián, so I’ll just mention some towns we’ve stayed in and enjoyed; Sigüenza, Soria, Olite, Pamplona, Burgos, Santo Domingo de la Calzada. We weren’t impressed with the city of Soria, but used it as a base to visit other places. In most of those locations we stayed at the Parador. In Burgos we stayed at Abba Burgos near the cathedral, and in Pamplona we stayed at the Pamlona Catedral Hotel. There are plenty of wineries in Haro.

A daytrip to nearby french towns Espelette and St Jean de lutz.
If you want to do some hikes, you should go to Picos de Europa.
The Cares trail, Fuente Dé to refugia Avila or a circular walk in Covadonga. One one trip our base was the town of Llanes, on the previous trip it was Canga de Onis. Lots of nice small towns and beach is around 1h away.

Plenty of great tips already!

If you have time, as others mentioned, it is really worthwhile to head a bit further west than Santander, to the Cantabrian coast west of Santillana (including Comillas, which has a Gaudí building, and San Vicente de la Barquera), and to the Picos de Europa.

Do not hesitate to just take the highway between Bilbao and Torrelavega (for Santillana del Mar / Comillas / San Vicente de la Barquera): the stretch of coast immediately west of Bilbao is not that interesting in comparison.

And you do not have to spend a night in Santander. Driving is fast and traffic jams are almost unheard-of, so you can easily reach the airport from, say, Santillana del Mar (30-45 min), or even Potes if need be (1h45)

We stayed in Hondarribia for a week and largely followed MikeBasque and Balso’s excellent suggestions. Hondarribia is a great location for accessing both French Basque and Spanish Basque regions. And you will notice in Spain that signage is first written in Basque followed by Spanish; in France, French comes first, Basque second.
Hondarribia (17,000 pop) is a lot smaller than San Sebastián (186,000) so you might prefer staying there.
Look at Comillas and Getaria. Even though Bilbao is a city, you should visit it. Do not bother going to Santillana Del Mar; we disliked staying there as it is very touristy. You may be using Santander airport but should includes areas beyond it too.
When looking at towns google the name and pop to see how large it is. Guide books may refer to a charming village but in reality it may be quite large.
Go to maribelsguides.com and print out the ones that apply to where you are going in Spain. She is American but has a home in the Basque region, knows it well and leads tours there too. These were extremely helpful to us while planning and staying in the Basque areas. Also, before you go, read “The Basque History of the World” which will give you the history of these ancient people. Very readable.