We did a similar drive a couple Octobers ago with a mix of highway driving and side roads. We drove in from Rome (more precisley Ostia, near the airport) to our rented home in Umbria near Orvieto
We chose to use the expressways to get past Rome traffic and to our place quicker. Once there, we made day trips in all directions. Roads are fairly well marked, although often not until the last second! We got used to passing our turns pretty regularly. Also, many of the road signs refer to towns or villages but with no compass direction. If you will be relying on GPS, this is less of an issue but our phones were spotty in many of the remote regions. We carried a detailed printed map for backup.
If you choose to take the eastern route north through Orvieto, some notable stops along your way are:Civita di Bagnoregio
is an incredibly charming and tiny hill town. It's only accessible by a long footbridge. It's a must-see in my book. Montepulciano
has great wine, food, and a village worth exploring. Orvieto has an impressive Duomo and many excellent restaurants and great sightseeing and shopping. There's a very interesting underground history (in the literal sense) there as well.
While these are probably more than just roadside stops, they may be something to add to your travel days. Enjoy the trip! Italy is lovely!