Anyone recommend better/best ways/airlines to get to Sicily from U.S. midwest?

The train connections to Sicily are poor, so for most people, a flight is what makes sense.
Some flights are seasonal, and winter is low season, so that probably explains some of your problems. Also, not all flights are daily.
Which destination are you looking at? There's not only Palermo; Catania also has many flights.

Our experience getting Sicily -

There are connecting flights in Germany on Lufthansa to Palermo. We have also flown from Rome to Palermo.

We just flew Munich-Zurich-Palermo last month.

If you can fly to Munich or Frankfurt, Germany or Rome Italy, you should be able to get a connecting flight.

Sicily is NOT easy to get to for sure. We've gone because that was the ONLY place we were visiting, it wasn't part of a longer trip.

Yeah its a pain. Even looking at connections in other cities in Europe, flight times could be 20-40 hours. We traveled from in February 2019 Kansas City to Palermo via Minneapolis (Delta/Alitalia) so two stops (MSP and Rome) So you could probably do it in one from MSP. We found it made a difference if we shifted our departure day one way or another in the Search engines, different flights with shorter times became available. Our return was from Palermo via Munich and Chicago on Lufthansa so you could check United (partner).

We are planning to go to Sicily next May and have thus done a lot of research. There are direct flights from Milan and Rome to Sicily so I have played with flying in and out of those cities on different tickets. My daughter and husband are going with us from Atlanta and i discovered that Delta will fly with ITA connections to Sicily. I found that flights to Sicily from Atlanta were not available for sale for May yet but could see them in calendar for Fall. Maybe that would be possibility for you, since Minneapolis is big Delta hub too.

Also look for both Palermo and Catania as I found different availability.

But yes, more challenging (and expensive) than I expected.

We flew United from Dulles (IAD). Flying to Catania we had a layover in Munich and coming back the layover was in Frankfurt. The flights for a couple legs of the trip were operated by Lufthansa.

What they said! However, if you don't have any experience with Frankfurt, I'd highly recommend you find another route. The airport is huge and transfers take a long time. Very unpleasant. Munich is our preferred transfer point. Nice airport; big but manageable.

I took the night train from Rome down to Sicily in 2015. I was in a couchette rather than a regular sleeper car; I know the latter are nicer. However, my experience was utterly miserable because of the constant jerking of the carriage from side to side. It felt as if the problem was the rail lines more than the couchette carriage. I got not one wink of sleep. I cannot imagine the misery of doing that right after you've taken the overnight flight to Europe.

I believe Catania has more flights than Palermo, so definitely check it as well.

So you could probably do it in one from MSP

The MSP to Rome nonstop is no more.

Seeing $1000 2 stops from MSP via AMS/FCO/PMO or CDG/FCO/PMO in 14-16 hours, that's as good as would be expected. Some days also AMS/Milan is offered, and New York/Rome is rather cheap though 18 hours.

https://www.google.com/travel/flights/search?tfs=CBwQAhoeagcIARIDTVNQEgoyMDIzLTAyLTI2cgcIARIDUE1PGh5qBwgBEgNQTU8SCjIwMjMtMDMtMTVyBwgBEgNNU1BwAYIBCwj___________8BQAFIAZgBAQ

Thanks, all, for the great advice. We DID find a Delta flight out of Minneapolis (through Amsterdam) to Rome. Saw lots of cheap flights from Rome to Palermo on ITA Airways, so we will just book those separately. The mid-March return flight from Rome to Amsterdam on ITA had no way to book seats, yet, and listed 4 different Airbus bodies as possible, so I'm assuming they haven't assigned one. (A little iffy for hitting our return flight from Amsterdam to Minneapolis, but hoping we'll see it open up before we leave. Otherwise, at least we'll be in Rome (flying on ITA to Sicily) and can ask at the ticket counter if we can get seat assignments three weeks ahead. As always, appreciate the great experience that people are willing to spend their time giving.

You didn’t mention if you’re going to make the trip to Sicily all in one day. So, i will just mention that coming from the west coast, we did LAS -FCO through LHR on British Airways. We then did an overnight at the Hilton Hotel that’s an easy walk from the terminal and then caught an ITA flight on a separate ticket the next day. It worked well for us and took the edge of jet lag.

The most options are via Rome (FCO). If you can, fly Delta, which is an ITA Airways partner. MSP is a Delta hub, so you may have options from there. You are flying in winter however, therefore non stop to Rome will be only from the East Coast (New York, Atlanta)

We've been to Sicily twice. Each time, I found the cheapest place to fly from our home airport to Europe and then got a flight to Sicily from there. First time it was Brussels and we spent a night and then flew to Catania. The second time it was Munich and we spent a night (in Freising) and flew to Palermo the next day.

Consider breaking up your trip by adding a couple days on each end in another city in Europe. One of the things I often do is look at the Wikipedia pages for the airports that I need to get to. For example, here is the wiki page fpr Palermo Airport:
https://en.wikipedia.org/wiki/Falcone_Borsellino_Airport

See what cities have direct flights to Palermo. Are ther any you’d like to spend a few days in and that you can get a flight from Minneapolis to?

For example, I often start my trip with a couple days in London, before flying to my ultimate destination, There are many low cost carriers that fly from London and I get the double benefit of enjoying a few days in London before traveling on.

We are doing the same (flying out of O'Hare) and while we can do it, it isn't cheap. Looking for June 2023. It looks like on the way to Palermo we will have a stop most likely in Munich, but still just checking on flights at this point. We are stopping in Rome for 4 nights after our Sicily tour so are booking the flight from Catania to Rome separately as it is much cheaper. We are United members so generally fly them or partners like Lufthansa.

We are leaving this month from the Midwest. We are going to fly to Newark New Jersey the night before, and then fly direct to Munich, but you could do the same and fly direct to Frankfurt and then take Lufthansa to Palermo or Italian air.

We are leaving this month from the Midwest. We are going to fly to Newark New Jersey the night before, and then fly direct to Munich, but you could do the same and fly direct to Frankfurt and then take Lufthansa to Palermo or Italian air.

We were initially going to go from Chicago, direct to Rome. These are all on United Airlines, and good flights. Then take ITA Out from Rome to catania

Here is. 15 hr route we chose
Google Flights Search results

Departing flight
Wed, Mar 1

4:20 PM
–
2:25 PM+1
Delta, Air France, ITA
15 hr 5 min
MSP–PMO
2 stops
CDG, FCO
551 kg CO2
Avg emiss

ps a good excuse to stay over in Paris or Rome for a few days or a Best of Tour.

We always fly to Rome and change planes there for Catania or Palermo. Fly to nearest city with non stop flights to Rome.

Yup, it was the Delta flight from Minneapolis to Amsterdam (KLM to Rome); then we'll book separate ITA flight from there to Palermo. Doing RS 11-day Sicily tour (first time on a guided trip, but we didn't care to drive in Sicily). Since we're leaving end of February from MN, we're definitely getting travel insurance in case of heavy snow. We like flying IcelandAir from Minneapolis through Iceland to Europe because of breaking up the long flight time, but not much available that would work. Got extra legroom seats to make up for the longer flight. Personally, I hate takeoffs and landings, so not thrilled with 8 by the time we get to Sicily. It might be Xanax time;)