Northern Italy Trip in September, Milan or Como as Hotel base before heading to Venice?

For Lake Como, I would not stay in the town named "Como." Varenna is on the train line and thereby ideal for a day trip via the Bernina rail route into Switzerland as well as for short ferry rides to Bellagio and other places on the lake. Although it is doable, I would not want to travel from Lake Como to Milan for a full day of sightseeing in Milan and then head back to the lake for the night. These trains are sometimes quite crowded with numbers of people standing. I appreciate the desire to minimize hotel/city changes with one base, but I would find it much more enjoyable to stay at least one night in Milan for the Milan sights. If you want to see DaVinci's Last Supper, you need to reserve timed entry tickets several months in advance. If you have at least a full day or parts of two days, your changes of getting tickets will be better. You might stay in Milan the day you arrive since you would need to take a train into Milan to get one to Lake Como (if you are going by train). Or you could stay in Milan the night before you go to Venice as you will need to take a train to Milan to get the train to Venice, again, assuming you are traveling by train. If you are renting a car, you won't want to have the car in Milan.

It may not be an popular choice, but I would consider staying in Como city; you can tour the lake from there by ferry and it's. lively city with great restaurants and shopping....and much less jam-packed than the ocular towns that have easy access to Milano, like Varenna.

You can take a ferry and reach Bellagio in an hour or so...

You will need to be in Milan or near MXP the night before departure.
I would spend first few days at Lake Como- day trips to/from Milan from there would be a pain as transportation is limited and extremely overcrowded
Next train to Venice
End in MIlan- give Milan at least 2 nights.
If you are interested in the Last Supper be sure to stay on top of when those tix go on sale. They sell out almost immediately.

Another option is Venice- Milan- then end at Stresa on Lake Maggiore. There is a direct bus to MXP from Stresa (actually closer than Ilan)
Stresa won't be near as crowded as Lake Como. Take the train into Switzerland

Venice hotel
Hotel Ala- can't beat the location, just steps from vaporetto with no bridges to cross. In a quiet campo, excellent bkft, great staff and roof top terrace. Quick walk to the sights
https://www.hotelala.it

I suggest staying in Varenna on Lake Como. There is a train station there. You could either walk to your hotel or take a taxi or uber. We loved staying at Hotel Albergo Milano. An easy walk to the ferry terminal. And they have an awesome restaurant, La Vista. You should make reservations.

In Venice, we stayed at Hotel Agli Alboretti located in the Dorsoduro district, which is a much quieter area than San Marco Piazza. We loved staying here. It's about a 1-minute walk from the vaporetto stop at the Accademia Bridge. About a 5-minute walk from the Zattere (seaside promenade on Guidecca Canal). And about a 20-minute walk from St. Mark's Basilica.

Thank you for the advice and recommendations. We will have a driver for most of the trip so train lines are of less importance. We will be staying the last night in a hotel close the MXP to make the next morning's flight home much easier or maybe we could end our trip in downtown Milan and cover the main attractions at the end of the trip. Any recommendations for hotels in Milan?

Staying on the very busy Grand Canal can be noisy. We love the Cannaregio area, and the hotel Ai Mori d'Oriente, in such a charming area, without the crowds. Have a great trip!

Milan hotel
Duca di York
https://www.ducadiyork.com/en/