driving from Madrid Spain to Lisbon Portugal

What time of year, and how long do you have to make the drive?

If this is to be a one-way drive, are you aware that you will probably pay an extremely high international drop charge?

ViaMichelin lays out three possible routes. Estimated driving times are similar enough that--assuming you aren't trying to make the drive in one day--you could reasonably decide to take the route that sounds most interesting to you.

On or near the northern route: Segovia, Avila (the least interesting stop for me), Salamanca, Ciudad Trujillo (non-touisty walled town), Guarda (Portugal).

On or near the middle route: Plasencia (attractive historic center)

On or near the southern route: Trujillo (rather forgotten town in lightly visited part of Spain, home of several important explorers; considerable historic architecture), Caceres (very impressive UNESCO-protected historic center--a stunning place with few tourists), Merida (Roman ruins and archaeological museum, but not a particularly attractive town otherwise), Evora (Portugal).

For me there's more to see along the southern route if you take into account that it's east to visit Segovia, Avila and even Salamanca from Madrid. But the northern route also has some good stuff. I'm less sure of the middle route, but I so recognize the names of some Portuguese cities along the way; I just can't vouch for them.

Thanks so much for your quick reply!!

I forgot to add we will be in Spain around May 23, 2020 and heading over to Lisbon, Portugal. We would like to make the drive in one day but are flexible to stay over along the way.

Any concerns with parking the car once we arrive in Lisbon?

It will probably take you the better part of one day to drive from Madrid to Lisboa, between checking out/in to your hotels, getting in/out of the two big cities, the actual driving, getting petrol etc.. I would not count on seeing much if you plan to make the drive in one day. If you have enough time for one stop to grab lunch and take in a few local sites, here would be my recommendations:

In Spain:

Cáceres - The old town of Cáceres is a UNESCO World Heritage Site and has a mix of Roman, Islamic, Gothic, and Renaissance styles.

Mérida - Has the best Roman ruins in Spain, designated a UNESCO World Heritage Site, the ruins are found dotted throughout the modern city of Mérida.

Badajoz - Capital of the Moorish kingdom, the Taifa of Badajoz. It has a nice Moorish historic quarter. The town is dominated by the Alcazaba, a 9th century fortified Moorish citadel.

In Portugal:

Evora - charming white-washed town with impressive roman ruins

Edit to add:
Listen to Acraven above, don't underestimate the cost of dropping off a rental car in another country, the fee could range from the mid-high 100s of Euros.

Another endorsement for Merida. Stopped on our way from Madrid to Portugal in 1987 and we are still talking about it.

"Any concerns with parking the car once we arrive in Lisbon?"

Yes!

Thanks all. We have decided to fly! Your input was valuable! Happy travels!