Should I book the flight in and out of Nice?

Nice would be a good base for Nice. Ventimiglia, just across the border in Italy, is about 45 minutes away by train. Between them are several attractive French Riviera towns, plus Monaco.

Certainly an "open jaw" itinerary makes more sense than returning to Nice from Italy. Whether Rome is "too big a trek" really depends on how long your trip is. As you know, there's plenty to see between Nice and Rome if you have time. How much time do you have?

I would think that the effort to get to Rome being too long of a trek would depend on how long you have in your trip and if you are working your way in that direction anyway..................if you have 3 weeks and you are spending 4-5 days in the places progressively in that direction, that doesn't seem to bad for me, but if you aren't going any farther south than the Italian Riviera on a short trip, stick with the closer ones.

From Nice, you can easily drive to the Piemonte region in Italy. Stay in the wine villages that surround Alba.
You can also stay in France and head west into Provence with its charming villages.

Gosh you guys are quick and the best! We will have 11 nights.
Likely impulsive act (but usually those make the best memories?!) but I booked the flights into Nice and out of Rome! This is the earliest I've ever booked flights so lots of time to strategize and plan!! Roughly thinking 2 nights in Nice ... 4 nights headed towards Tuscany ... 4 nights Rome ... can't wait to read through the forum and hear the expert advice from you all!

Driving straight from Nice to Rome is about 700 kilometers, or 430 miles, so easy if you spread it over days and stop along the way. But you won't want to pay the big fee to drop off a car in another country. You could take a train across the border and get the car in Italy, or just do the whole trip by train, depending on where you want to go and whether you want to drive. But you have plenty of time for this "trek." Have fun planning it.

My wife, daughter and I are flying into Nice from Paris, and several days later flying from Nice to Rome. Then home to the West Coast from Rome. We will use Antibes as a base, which is about 20 minutes by train or bus from Nice. We have planned to visit Eze, Menton, and of course Nice, and ride the Train des Merveilles (train of wonders) up into the mountains as far as Breil-sur-Roya (the train goes further to Tende, but that town didn't look very interesting to me). These are easy day trips, which is ideal for us as our daughter is young.
An earlier iteration of the trip had us staying a couple of nights in Nice and Menton, then traveling along the Gulf of Genoa in Italy, stopping in Ventimiglia, Camogli and Porto Venere before reaching Rome. Train to the smaller places like Camogli seemed very difficult, and the cost of renting a car one-direction was prohibitively expensive. I was surprised that the stretch of Italian coast wasn't as linked together as the French coast is, at least as far as I was able to determine.
The train ride from Nice to Rome is about 5 hours, which we would have done if our daughter wasn't along. The flight is one hour.

I’ve flown in and out of Nice. The airport is fairly small, just down the coast from the hurt, and is easy to use. A few years ago, we flew in to Rome from the USA, and after time there, made it to Florence by train. We then went by train from Florence to Nice, with a number of transfers along the way, and it took ALLLLLLL day.

Base yourself in Nice. I like the area by the old port, near Place Garibaldi (corrected). Alternatively, the neighborhood near the Liberation Market is my next suggestion, and by Place Messena. Finishing your trip in Rome is a fantastic idea, but split your time up getting there - don’t try to make it in a single day!

The trek down to Rome is pretty large --- the worst train leg is through to Florence, over six hours at best (it used to be faster but the Italian train system has cut back on the direct trains). You can pick up a car in Ventimiglia or san remo and take the drive along the coast or cut inland through to Florence (through Piemonte). The route depends on your interest. Or you could skip it all and take a low cost flight to Florence.

Nice makes the best base if you plan a lot day trips. It is generally more convenient to stay in the Carre d'Or or around Place Massena (which is not the Port area), to be convenient to the main station and tram line intersection (but not too close).

Twice we have stayed with friends in Antibes and taken day trips into the Piedmont region of Italy. Ventimiglia, San Remo, Apricale, and Dulceacqua. It was also convenient for all the towns along the Riviera, as well as going into the Maritime Alps and Provence.

I wanted to correct my previous post --- Trenitalia is now planning to restart the Nice-Milan direct route, from June, with a tourist oriented line, but unfortunately not as a high speed train. It was stopped after the start of the pandemic. This start date seems to be a target, and there is little other than press reports at this time. This should cut down the # of transfers to get to Florence and beyond (though it appears they will have to swap out crews at the border).