Airline advice between IAD (Dulles) and Milan airports

If Zurich and Venice are included in the plan, a multi city flight itinerary would definitely be better, the direct flights are just a bonus. So, it depends on your decision on including them.
Sometimes a layover can’t be avoided and just make sure yours is long enough for big airports like Paris, Frankfurt, Munich.

If a layover is necessary, how much time should I allow to change planes without stress?

The airlines dictate this, but around three hours is a safe bet in summer, a little bit less than that’s okay. Book it all on one ticket, as if you are doing two separate legs you might need additional time.

I focus on the transatlantic flight since that's the one that I want to search for comfortable seats. Use flightsfrom.com to find nonstops from your destination city (MXP for example) to a nearby gateway that connects to IAD. Now do that in reverse to see if there are easy connections from your European gateway to MXP. Repeat the process for the other half of your open jaws.

Flights within Europe are cheap and easy. Fast trains open up lots of gateways in and out; particularly useful linking Zurich.

= A layover is fine. I have done single night layovers but I often regret them as expensive time-wasters. It really depends on the flights and how easy the airport is to access the fun aspects of a particular layover city.
= But a Direct to MXP is better. What is your vacation time worth per hour?
= I like to do my trip to Europe as an overnight so I can adjust quickly the the time change. Conversely...
= Flights get increasingly delayed as the day rolls on. Your best bet is always a flight that uses a plane parked overnight.
= Don't be penny-wise, pound foolish on your flights. A cheap flight that exhausts you our forces you to buy an extra night in a hotel room isn't a bargain.

A few years back, we flew into Zurich, took the train to Chur and the next day took the gorgeous Bernina Express to Tirano and connected to a train to Varenna. I'd do it again!

Fly out of Milan or Venice to go home. Check the flight times out of Venice before you decide. I've been able to get midday flights out of Venice, but many forum folks report that their only choice is early morning. An early morning flight from Venice would be challenging.

United has direct flights IAD to Venice and direct flights Zurich to IAD

That’s a no brainer for me

Into Venice easier than out of
Train to Milan
Trsin to Como
Train to wherever in Switzerland-you can even stay in Lucerne night before departure

Book as a Multicity trip inder “Advanced search”

IAD is a United Hub so you should have several connections to Frankfurt or Munich (Lufthansa is a United partner). In any case there should be plenty of connections also through Amsterdam (KLM hub) or Paris CDG (Air France hub). Air France-KLM is a partner of Delta.

My recommendation is to try to fly to Milan Linate (LIN) instead of Milan Malpensa (MXP). Milan Linate is only 20 min taxi or bus ride to the Milan Centrale station where you can catch a train to Varenna. Linate is also small and easy to navigate. Malpensa airport is large and very far from the city (a 55 min train ride is required to reach the city).

LIN handles only intra Europe flights but has a ton of flights from Frankfurt, Munich, Paris CDG, Amsterdam, and I think also a few from Brussels. None from Zurich. Flights to Germany may be operated by Air Dolomiti (symbol EN), a regional airline part of the Lufthansa group.

In terms of layover preference I like Munich, Amsterdam, Frankfurt the best. They are all very easy to navigate. Frankfurt may require some long walks however, depending on gates used by your flights, since the Terminal used by United and Lufthansa is very long (shaped like the two blades in a pair of scissors). Paris CDG is humongous and requires the longest to make a connection (2 hours minimum).

I would prefer flying to Linate via any European hub over flying to Venice or Zurich, even if non stop. Flying to those cities will prolong your trip by several hours, especially Zurich.

Could you clarify if you are actually interested in visiting Venice and/or Zurich?

I read your post as a yes (“possibly”)

Or are you only interested in Milan and Como?

I flew roundrip from IAD to Milan MXP on TAP Portugal airlines with a stop in Lisbon. because this was, by far, the cheapest deal for me (in fall 2024) . I know Lisbon is not a favorite airport and sometimes has delays, but I have used TAP for several different trips and not had any problems, plus I get to have a pastel de nata pastry treat. Before returning to Milan, I spent 3 nights in Varenna on Lake Como at the end of my trip, including a scenic daytrip on the Bernina train to Pontresina.