Getting to Venice airport for a morning flight

I'll defer to others on whether this is even possible...but for something like a flight out, I'd book a confirmed water taxi. Great experience, and you'll know you're going to arrive on time.

Our flight out from Venice will be at 6:30 am. (Early flights seem to be common increasingly common.) We’ll be staying Cannaregio and I understand this is a convenient location. How have others handled this?

Is your flight direct to US?
If not getting there 2 hours ahead is fine

Official Water taxi

https://www.motoscafivenezia.com/en/

Or vaporetto /bus combo
I think first bus from Piazalle Roma is 4:20

No, the Alilaguna will not work for the OP. The earliest boat on the Orange line would not get you to the airport until 7:49.

The Line 1 vaporetto could pick you up at Rialto Mercatomat 4:58, arriving at Piazzale Roma at 5:14, and you could take a taxi or bus from there. They won’t get you to the airport until 6 or later, but that should be early enough.

Otherwise your best choice is a water taxi, which is probably what we would do if staying at that location.

You will find taxi cabs at Piazzale Roma that can take you to the airport directly. They're fast and efficient.

Last trip, we were leaving later in the morning and just took a bus to the airport from Piazzale Roma.

Those 6:00 a.m. flights back to North America are killers. We refuse to take those early flights as there are often mid morning flights where we don't have to sit around 4-5 hours in a gateway European airport until the long haul flights west leave mid day or slightly after.

I agree with David, take a water bus to Piazzale Roma (there is a night service) and get on a land taxi to the airport. Any problem during a water taxi ride in the early morning leads to you missing your flight home.