My first thought is, make sure you are OK with the hotel rates during Feria de Abril and Santa Semana. I remember my Seville hotel had three rates: low season, high season, and Feria/Santa Semana (called "bonus season" on some hotel websites, and when you see the prices you'll understand).
Next, start picking first and second choices among the "Rick's Spain highlights," and also research places he doesn't talk about. As said above, Spain is a big country, and you can't see everything. As you research, start making an estimate of how much time you will want in each place. You should know that the question of "Madrid vs Barcelona" is very divisive; some love both, some hate both, and many have a strong preference for one over the other. As you rough out an itinerary, you will probably find that you have to skip some places in order to have enough time in the others (the reason to have a priority list). With 3 weeks, however, you can certainly see a lot of the places Rick features.
Third, consider transportation. For getting from Barcelona to Madrid to Seville, AVE (fast trains) are best, and trains or buses work for many towns, but a car allows you to get to smaller towns more easily. Don't overlook the option of a flight within Spain (from Barcelona to Granada, for instance, it can often be the best and easiest way).
From Spain to Italy, you will want to fly, unless you want to stop off in France (the train ride is VERY long with multiple changes). So, you will also want to think about flight options as you start planning; you can use Skyscanner to find these. You will want to end your Spain trip to enable an easy flight to Italy (I don't know if Seville has flights to Italy or if you would have to change in Madrid or Barcelona).