pick up car after Cinque Terre? drop car before Modena?

Car Pick Up: LA SPEZIA.
From Manarola take the train to the nearby city of La Spezia (just minutes away). From La Spezia Centrale station take a taxi to the rental car office (I think only Avis may be close enough to walk from the station).

Car Drop Off: MILANO MALPENSA AIRPORT.
Do you really need 3 nights in Modena? It's up to you, but Modena can be visited in hours and I don't know how long you intend to visit Maranello (never visited Ferrari factory, so I don't know). I don't know how many days you have at your disposal, but this is what I like to do when I fly out of Milan: keep the car and drive all the way to Stresa on lake Maggiore. Spend 2 nights there before the flight home. The morning of your flight leave your Stresa hotel one hour prior to the time you need to be at the airport, drive from Stresa to Milan Malpensa airport (45 min drive), drop off your car at the airport and depart. If you can, try to prolong your vacation so that you have at least 3 nights in Stresa, even better.
I think 2 nights in Stresa are a better choice than one at a Malpensa airport hotel and you can probably cut one night in Modena.

Roberto, Thanks ...that is a great idea ... is it a stressful drive? It will be our first time driving in Italy, so I don't know how to judge our comfort level. I will definitely check out Stresa. How much time will we need in Milan Mariposa? The usual 3 hrs for international flights ... or more?

Doris,

For driving in Italy, keep in mind that each driver will require the compulsory International Driver's Permit, which is used in conjunction with your home D.L. You can obtain those at any AAA office for a small fee. You'll also have to be vigilant to avoid the dreaded ZTL (limited traffic) areas which exist in many towns in Italy, as there are hefty fines for violating them. A GPS and a good map would also be prudent.

Siena to Modena is all freeway.

Not stressful but remember that in Europe the left lane is passing lane only and you must clear it and move to the right after passing. No cruising in the left lane is allowed (you will experience some stressful tailgating if you try). Also no passing from the right.

Modena to Stresa is all freeway (except for the last few miles on a curvy road across the hill).

Driving in Tuscany will entail lots of curvy two lane highways in the hilly Tuscan countryside. Just be careful as many highways are not too wide and have no shoulder. I'm sure you have similar roads on the Appalachians.

If you fly directly from Malpensa to the U.S. 2 -2.5 hours are more than enough. If you connect somewhere in Europe first, even 1 to 1.5 hrs is sufficient.

The airport is Milano Malpensa (I suspect sn auto-correct came up with Mariposa), in August I needed every minute of two hours to get through it due to construction detours inside the airport, may be better now, but it looked like a long-term major project.

Thanks for all that helpful advice regarding driving in Italy (however, I get stressed EVERY time my husband drives...haha...). And at the airport, we plan to be early ... because we unintentionally always end up running late!

Stresa seems like a lovely option and we don't have a super-early flight (Malpensa - Sunday 10:45 am). But if we do not get to Stresa, what might be a second option for dropping off the rental?

If you don't have your own car in Modena, there is a local bus to Maranello, but it only runs every 1.5 hours. Give Maranello a full day - there are two good museums, with a bus between them, and a noontime opportunity for a bus tour of the test track. If you are also going to reserve a driving opportunity, then you'll be plenty busy. Bologna is an enjoyable day trip, but is not a top recommendation as the old town is fully hemmed in by uninteresting modernity, and would not be a place to use a car.