Lagos Maggiore to Como - driving from Lucerne

With a car, I would stay on the western shore of Lake Como. If you do so, the best route is the motorway from Stresa to Como town, then SS340 up to, Menaggio for instance. Try to find a hotel close enough to a ferry pier, so that you can do without the car while visiting lake Como.

Grazie mille, Balso. Your response was very helpful. I have now booked 3 nights in Stresa and 4 nights on the west side of Lake Como in Tremezzina. We'll walk about 10-15 minutes to catch the boat in Tremezzo.

The main docks in the midlake (the ones with the most frequent ferries, including the midlake shuttle ferries) dock in Varenna, Bellagio, Menaggio and Cadenabbia. Tremezzo will have fewer ferries.
If you are committed to staying in Tremezzina, you are better off driving an extra one minute from Tremezzo to Cadenabbia. There is a parking lot for ferry travelers along the lake in Cadenabbia.
My preference however would be to stay in Menaggio, you can just park the car at one of the 3 parking lots in town, leave it there the whole time, and walk to the ferry when you need. Menaggio is also very lively and in summer they even have nightly classical music concerts on the main piazza (Piazza Garibaldi). The walk from Piazza Garibaldi to the Menaggio Ferry dock is only 5 minutes to the south next to the Grand Hotel. Last time I stayed in Menaggio I stayed here:
https://www.hotelgarnicorona.com/
In previous trips I stayed in Bellagio, which is great but Menaggio has better parking options.
There isn't significant difference in travel time from Stresa to any of the towns in the midlake. But with a car I prefer Menaggio (you can also visit Lugano easily from there).
PS: If you stay in Tremezzina, read about the last days of Mussolini. Tremezzina is where the Partisans during the Resistance held him prisoners after capturing him (he was trying to escape to Switzerland) and where he was executed, before taking his body to Milan where he was hanged upside down. There is a plaque in front of the villa where that happened.

Roberto, that is wonderful advice about the frequency of the boats and parking availability. At least we aren't too far from Menaggio to drive there for more frequent boats and parking. Grazie mille! There is definitely something to be said about the partisans in Tremezzina. Bloody good for them.

We have stayed multiple times in Cannobio on Lago Maggiore at Hotel Cannobio. You can buy a combo ticket for the ferry to the Islands from there. Loved Isola Bella. We have always driven from Switzerland to Cannobio and, although you can't park in town, you can drive to your hotel to unload and then park nearby. It has never been an issue, a little tricky the first time maybe, but doable. We have also stayed on Lake Como several times and prefer Varenna. We stayed at Hotel Olivedo. You can then take the ferry to the other towns including Bellagio. Can't help with the driving details but am sure you could find them online.

You are renting a car in Switzerland and plan to return it in Italy?

In Stresa, the top floor room at the Milan Speranza du Lac has a large roof-top terrace; location across the street from the port.

We are flying in and out of Milan so the car rental works. We're spending a week in the Valais and on from there.

Just to make sure, are you planning to drive straight to the Valais after landing in Milan?
The drive is not that short, and driving over Simplon pass after an overnight flight feels dangerous to me!
If so, please consider either:
- safest option, staying somewhere close to Milan for the night - Orta S. Giulio would be lovely.
- using the car train under Simplon pass, from Iselle to Brig. The wait can be long if you miss one because it only runs every 90 minutes, but it reduces driving time to 1.5 hours from Malpensa on easy roads, and the train ride is less than 20 minutes vs. approx 45 minutes on the pass road

We did not have this information, Balso. Yikes! A car train? We had initially considered driving to Chamonix and overnighting there but decided to add the nights to our stay in Sion and day trip to Chamonix. We are used to day tripping and don't mind driving. Perhaps you can advise more about this plan?

It is generally considered unsafe to drive for more than 2 hours or so after a "red-eye" flight eastwards. Actually, even when I go westwards I hate to do so.
Driving to Sion from Milano Malpensa over the Simplon pass exceeds that by an hour or so, and the pass road is tiresome even though the road is of a very high standard and not too twisty.
The car-carrying train (all info here: https://www.bls.ch/en/fahren/unterwegs-mit/autoverlad/brig-iselle) would help you break the journey and make it safely to Sion if you are unwilling to stop somewhere en route (which would be the best option).
Another option is the Great Saint Bernard Tunnel, but that is quite a detour, I would not recommend it.

Thank you for this information about the car carrying train. I will check it out. I've also contacted our Sion host for their input. We hoped to take a day trip from Sion to Chamonix and so we're checking to see if that is realistic.

Balso, I am sorry to bother you with this question, but I wonder if you could possibly tell me which train line would be appropriate for our car carry option from Milan to Sion? Many thanks!

You have to drive to Iselle, about 1.5 hours from Malpensa airport on the motorway. The car-carrying train starts from there, and takes you to Brig - all info is on the link I shared earlier. After Brig, it's a less-than-1-hour drive to Sion.
Your Swiss host will certainly say that this is unnecessary, because the Simplon Pass road has been improved a lot in the past 20 years or so. But it is still a relatively twisty, 2 (wide)-lane mountain road, that goes on for 45 minutes. It is not one I would like to drive after a near-sleepless night on the plane.
The main issue is really the frequency, only every 90 minutes can mean a longish wait. It used to run every 30 minutes, but successive road improvements made the train shuttle less popular.

As for a day trip from Sion to Chamonix: that's totally realistic; a short section of the drive up from Martigny used to be "interesting" but I think it's been widened since. In any case your location states that you're from Washington state so you seem likely to have some mountain driving experience.

Thank you, so much, Balso. We're addressing this in the wrong post but, oh well. Once we started! Thank you for specifying where to get that train. I was quite confused. We'll have to see how things line up. We still haven't reserved our airfare yet. I was awfully glad to know that we could day-trip to Chamonix from Sion! Yes, you're right that being from Washington State we have mountain passes that we've driven through. Many of them up and down the coast, as well as coastal highways. Most of them are at wide two-lanes or four lanes. Flying from the West coast is a long flight to Europe and we actually do get a good 5-8 hours of sleep. After several trips around Europe, we have been fine with driving. Although, we keep getting older and, if we didn't feel that way at any point in time, we'd find a hotel.

Glad to help.
You could just "play it by ear", really: the car-train does not need or take bookings. If you're feeling alert, you can skip it, but if you start getting tired, you now know it's there.