drive from Lisbon to Madrid

Do you mean Nazare?
Just in case the car is not yet arranged, do you know there can be a high fee to drop off in a different country?
Caceres would be a great stop. Definitely pass through Alcantara to see the famous bridge.

I have not been there, but Plasencia sounds lovely.

And just in case the FLIGHT has not yet been arranged, you might want to compare your drive-versus-fly costs (including the potential cost to cancel or change your flights). If you haven't accounted for the one-way car rental drop-off fee, this might be a longer, much more expensive drive than you may have expected.

When I first investigated options for driving a rented car from Portugal to Spain, the quoted one-way drop-off fee was over €800...and that was before the current sticker-shock we all experience for most things. You will want to take a close look at the costs for this and be sure that driving makes sense.

I’ll assume you rented the car in Spain and are just returning it in Spain. My question would be the amount of time you intend to take for the drive since it would be easy to spend 4 weeks between Nazaré and Madrid.

Possible places to stop not already mentioned could include, Tomar and Monsanto in Portugal, Coria, Trujillo, Guadalupe, Monasterio de San Jerónimo de Yuste, and Talavera de la Reina in Spain. There are many other places depending on the route you take.

For an upcoming trip we have lodging reserved at the Paradors in Cáceres, Trujillo, Mérida, Guadalupe, Gredos, Almagro, Toledo, Oropesa, Jarandilla de la Vera, and Plasencia.

You do intend to be in Madrid at least the day before the flight, correct?

It is about a 400 mile drive. Unless you are doing it over multiple days, there is not a lot of time for 'visiting' on the way.

Knowing your time frame for the trip would be helpful