Cinque Terre --> Lake Como --> Zurich

I would skip Como as a base. If there's something specific you want to do in that city, you can day-trip there from either Varenna or Bellagio by ferry.

What do you plan in Zurich? It's an attractive city, but with little time in Switzerland, most people would recommend skipping it in favor of time in the mountains (such as in the Lauterbrunnen valley). Lucerne is more picturesque option than big-city Zurich if you want an urban rather than rural environment.

Are you planning to do a lot of hiking? (I'm guessing not since you're proposing to spend your Swiss time in Zurich.) Five days is rather a long time in the Cinque Terre.

My recommendation would be 3 or 4(if this is the start of your trip after a transatlantic flight) in CT, 3, maybe 4, nights in Varenna, the rest in Switzerland split between Lauterbrunnen/Murren and Luzern.

We went to Varenna in October and ended up looking at Tripadvisor/Booking when we were finding a lot of the places full.

In CT we stayed at Aria di Mare and loved it.
www.ariadimare.info

Option 3, the only choice! Maybe even one more day in Bellagio taken from Zurich.
Do not spend an overnight in the former silk making city of Como but use that time to stay in Bellagio. We have been there for extended stays four times. Varenna is nice but Bellagio has more dining options.
I have only flown in or out of Zurich, never stayed there. Maybe we should check it out next time!

Sounds like skipping Como (the city) makes sense. The train we'll take to Switzerland will likely be from Como, but good to know that it's not worth spending a night or two there.

We'll be doing a lot of hiking in Cinque Terre (hence the 5 nights there), after flying into Venice and spending 3 nights there. But maybe 4 nights in CT is enough?

CT + Lake Como seems like a good amount of time in "small picturesque waterside villages," which is why a bigger city like Zurich seemed attractive. Plus my husband's desire for "easier" travel grows stronger with every passing year. So, the "honey, we need to change trains 3 times to get our our destination" is just a harder sell these days! And he prefers public transport to driving.

But, definitely open to Luzern if it's a can't miss. I have been to Interlaken and surrounds, but that was in the 90's!

Always keep in mind travel times. This means your days can be consumed the more times you move with travel, hotel check-in, etc. Hopefully, your reservations can be cancelled without losses. If so, I would suggest this itinerary.

I would suggest 3 nights in CT max.

I would train and base in Varenna 4 nights and day trip Bellagio and Como.

I would then train from Varenna to Tirano and ride the Bernina Express to Chur. Stay 1 night in Chur.

https://www.myswissalps.com/berninaexpress/gettingthere

From Chur I would train to Lucerne for 3 nights. There are many things to do in and from Lucerne.

Then train from Lucerne to Zurich 1 night.

That should use your 12 nights.

After leaving Varenna are you planning on doing the Bernina Express? The views are incredible.
Altho I like one day in Zurich, I agree with the other posters that spending time in the Berner Oberland and Lucerne is much more enjoyable than more time in Zurich. And- skip Como itself.
Have a safe trip!

You could base in Luzern for your Switzerland time. From there, you could do a day trip to Bern. Another day trip option could be a boat across Lake Luzern, cog wheel train up to Mt. Rigi for stunning views. Very easy to do. Also, Basel could be a day trip option from Luzern. Very pretty, colorful town beautifully situated on the Rhine.

I don't think I am going to be able to get my husband to go for less than 3 full days in CT, since he really wants to do some hiking.

But, perhaps 3 nights Venice, 4 nights CT, 4 nights Varenna, 3 nights Luzern, 1 night Zurich could be a good revamp.

I wouldn’t bother with the hassle of changing hotels for 1 night in Zurich. The train from Lucerne to Zurich airport is just over an hour and super easy as the train takes you right inside the airport. If you wish to visit Zurich, you can easily do that as a day trip from Lucerne. Save yourselves some time and eliminate that last hotel change.

Further comments validating the Bernina route suggestion, based on minimizing transfers and maximizing travel pleasure:

While you “can” get from Varenna to Zurich with only one transfer, I do not recommend that, for the following reasons:

1) this route goes through the deep Gotthard Basistunnel—-at 35 miles, the world’s longest and deepest railway tunnel. You see nothing of the Alps scenery. And riding through those long deep tunnels is no fun at all.

2) Milano Centrale is a huge station and there can be a lot of walking between platforms for the transfer.

3). You really do want to head to Luzern, not to Zurich, for your last 3-4 days before flying out. You do not need to spend a night in Zurich at all, unless your flight is an early morning one. There are direct trains from Luzern right into the Zurich airport twice each hour, taking 1 h 12 minutes. So you save one train transfer right there (and a hotel change as well).

I really like the Bernina route that others recommended above. To minimize transfers on that route, I suggest taking the train northbound from Varenna to Tirano on the border, changing there to a Bernina Express train which goes to Chur with no changes. (The regional trains on this route will have 2 train changes on the way to Chur from Tirano). If you depart Varenna at 11:25, you arrive at Tirano at 12:52, giving you time for a light lunch before boarding the Bernina Express at 14:24. Overnight in Chur (a small, pleasant town) and the next day you head to Luzern. You can choose between a direct train (no changes) that takes 3 h 39 minutes, or a faster ride (2 h 17 minutes) with a single change at the Zurich main station.

I considered suggesting the Gotthard Panorama Express as a possible alternative to the Bernina Express route, in case you do not like that idea, but there are lots of changes on that route, and you would having trouble getting to Lugano in time for the once-a-day departure at 9:22. So I really believe the Bernina Express is the best fit for your travel wishes.

Our flight is at 9:35am, but an early morning train to Zurich looks like it could work.

I had been thinking of taking a ferry to Como, and then the train direct from Como to Zurich (or Lucerne), but now it looks like the Bernina Express might be the way to go.

Zurich has a very tiny old town so no need to spend more than a few hours in Zurich. It is a good place to window shop at the high-end designer boutiques, eat a meal and buy chocolate and that is it. Do not waste your time on taking a ferry on Lake Zurich.
What hikes do you plan on taking in the CT? The hike from Vernazza to Monterosso is probably the most scenic and the hardest. I would allow three nights for the CT and then move on to the Berner Oberland and hike there too i.e., the Männlichen to Kleine Scheidegg.

I agree with others that 3 days at most in CT. Avoid Como. If you base in Varenna give yourself at least 4 days there. Zurich is a fantastic city to change trains in. Otherwise go to Lucerne for urban, Lauterbrunnen valley for picturesque Alps.

Varenna is a better base than Bellagio, in my opinion, by having ready access to train and ferry alone. And far less packed with fellow tourists during the daytime hours. While CT is interesting it can be a bit of a nightmare as well with too many people during the day. It may be better since travel restrictions. That being said, since tourism is down overall and the cruise ships blocked, Venice for 4 days then Varenna for 4 days would be ideal.

Just my personal preference. Best of luck!

Thanks for the replies, all!

We've decided on:
3N Venice
4N CT (Riomaggiore or Manarola)
4N Varenna
4N Lucerne

Looks good!

I would suggest Manarola over Riomaggiore, as the famous Via dell’ Amore between the two villages will not re-open until 2023, after the major slide that wiped it out in 2012.

https://www.afar.com/magazine/cinque-terres-via-dellamore-hiking-trail-will-reopen-in-2023

So you cannot make the lovely 15-minute walk to Manarola; you must ride the train, or take a much longer detour on the higher paths. Those trains connections the villages can be very crowded—-we had to wait through two before we could literally push ourselves onto the train at Varenna to return to our hotel in Manarola after hiking from there to Vernazza.

Speaking of hotels, we loved La Torretta in Manarola:
http://www.torrettas.com/