2 days in Rome - is it better to stay right in the centre or a bit out of the crowds?

If Via Domenichino is the one by Santa Maria Maggiore, I would pick that one. You’ll be next door to a great church, Santa Maria Maggiore, and another really good one in Saint Praxedes.

I wouldn’t do the hop-on hop-off tour bus, Rome is pretty compact and walkable.

Perhaps consider the Prati area. It is on the Vatican side of the river, filled with locals and good food and a walk or short bus ride away from the main tourist zone. We have stayed in that area twice and loved it.

Best area is near the Pantheon.

I always pick a hotel based on convenience to the sights but also in a location that we will find enjoyable in the evenings. After a day of sightseeing we are not going to want to have to take a bus to get back to "the action". We found the area around the Pantheon/Piazza Navona ideal. I pick a hotel that is central but on a side street to avoid noise.

We always stay near Pantheon/P Navonna
Doesn’t get any more central
You can walk everywhere from there, even to Vatican although for early am entry you will want a taxi

With just 2 nights you don’t have time to waste getting into Centro storico from further out locations

There are lots of good cafes, gelaterias, pizza shops, good restaurants, bars and panini places in the Centro Storico

If you want a coffee you go to a “ bar” order/drink/eat at counter or grab a table and pay a bit more

HOHO bus in Rome not a good choice as the Centro Storico is all pedestrianized so bus is not going to get you close enough to see anything
You’ll spend most of your time stuck in traffic just on the outskirts of the Center

Rome is surprisingly compact and walkable, it’s a living history museum so walking let’s you experience all that close up

I’d probably stay in the center this time. Having accommodations in the thick of things means you have an easy retreat. Even noping out for just a few minutes can make a big difference. It’s a different equation when you have to spend extra time and energy to get back to your home base.

I stayed in an apartment on that street a few years back, and it was not at all noisy or busy.
I seem to remember there were no shops or businesses there at that time, maybe one restaurant , just residences.
We walked everywhere easily.

Rome deserves 4 nights just to see the highlights. If you only have two days at your disposal you should stay in the middle of everything. Via Marmorata is not that far, it’s near Trastevere, but with only 2 days, I would stay closer to the things you want to see.

According to Google Maps it's a 30 minute walk to the Pantheon. You may want to learn the bus system so you can do some of the back and forth on the bus, and also the Metro. Or use taxis.

I recall that the walk from the Colosseum to Monti was up hill.

You will be adjacent to Monti, so numerous options for meals and morning coffee.

I would not refer to Via Domenichino as being right in the center. For just two days, crowds may be preferable to longer walks to get anywhere.

I always think of the Pantheon as being the center of Rome

Thank you everyone for your responses and opinion. Now, I better see the point of staying right at the centre of things, or as close to it as possible. I will look into accommodation options near Pantheon area, but when I was looking before I couldn't find suitable options for us (price, beds, etc.).
..As for the HOHO bus, hm.. I didn't think about the traffic and that the bus may not be that helpful for getting us closer to the attractions we want to see. Good point! And will safe us some money, too.