Lisbon to Genoa

I haven't, and I rather doubt that anyone else here has.

I suspect the extreme gnarliness of the current schedule (see https://www.bahn.com/en/view/index.shtml) may be related to lower traffic due to COVID-19. I don't think there's always a 17-hour layover in Badajoz (Spain). But I can't imagine doing this by rail if your main purpose is transportation. If you have a lot of time and are planning to travel during the summer, I'd recommend traveling north to Galicia and across northern Spain. That would open up many fascinating cities and towns for you, and with a lot of stops, the comparative slowness of the trains wouldn't be so much of an issue.

Alternatively, you could fly from Lisbon to Madrid and hit the Spanish high-speed rail network there. That would be workable at any time of the year, though I think Madrid gets coolish in the winter.

The primary international trains departing Portugal are overnight trains to either Madrid or San Sebastián and the French border, both of which are currently suspended. The only other you might use is the once daily morning Porto-Vigo run. Even with those in place, it’s a very long ride, only worth doing by train if you have stops in mind along the route.

Traveling from Portugal to Spain isn’t ever easy.
Perhaps drop Portugal or fly into Spain for an easier start.

Dan, I have taken this route in pieces over the last few years. Your Lisbon to Madrid segment is the most difficult due to schedules, duration and lack of scenery. Let us know how much time you are allowing for the journey.

We did the Genoa to Nice portion last year (yours in reverse). Not too long time wise and some places were scenic.

Since you didn't mention your timing (length and time of year)... I think most of us are assuming you would make several stops on the way. Should be some great cities to visit on the route.