Driving from Lisbon to Sevilla- any must sees along the way?

Make sure you return to rental car to Portugal to avoid a large drop fee.

How about taking a direct bus from Lisbon to Tavira (4h) that is worth a stop and a direct bus from Tavira to Seville (2h). As Suki said you do not want to drop off a car in a different country.

The first place that comes to mind is Evora. And, Monsaraz. I’ve not made it to Monsaraz but Evora is definitely worth your time.

Make sure your car hire company knows that you will be taking the car into Spain (assuming you aren’t dropping it there). There will probably be an additional charge to cover both countries - some companies charge an additional rate for the entire hire period and others just for the number of days the vehicle will be in Spain.

You aren’t going to have very long wherever you stop, as Lisbon to Seville is around a 5 hour drive. Evora is fairly close to Lisbon. Other options would be Badajoz - the pretty Plaza Alta, La Alcozaba gardens, pretty squares and churches or Beja - the castle, several museums and the nearby Villa Romana ruins de Pisoes.

Thank you kindly, everyone! I really appreciate the input!

Vidigueira. The sweet town square has a municipal museum with well-done displays of vintage local items. If you enjoy ruins, the nearby ruins are not to be missed. The museum in Beja is worth a visit. We got some of the best grilled chicken and french fries near the Beja Se.