Rookie mistake, I guess

You should still be fine. Where are you going in Europe? I've found buying a bottle of water or two in a grocery store is an easy way to break a larger bill.

A grocery store of some size is a good suggestion. I'd try to go late in the day, when they're likely to a good bit of cash in the till. The won't want to give you a bunch of small bills in the morning.

I got Euro from an ATM last Fall in a smaller city in France and was given 50’s. There was no choice of denominations given. I tried using one at a restaurant which was very busy and they did not have change for my 25E dinner! The next day I tried at a grocery store, pulling the bill slightly out of my wallet and asking OK? The clerk looked at me like I was nuts and said (in English, lol) “No problem”. So…you should be able to get them changed by buying small items as suggested above. If the first place you try isn’t able to break it, try another.

By the way. I have not used much cash the last 4-5 years. I’ve used Apple Pay almost exclusively. I got cash last Fall as I was on a tour and eating with others so it was sometimes easier to pay cash.

Cash is used much more in Europe than the US so a 50€ note is much, much more common there than a $50 note in the US.

I’ve had no problems getting a hotel (or businesses) to provide change.

You will not have an issue whatsoever changing 50€, 100€ or even 200€ bills. I have mostly 50€ and 100€ from my past trips. People are more likely to carry those, than 20€ bills. Just go to any store and buy something of smaller value and they'll give you change. One day, over 10 years ago, I had a few 500€ notes in my wallet so I asked the shop where I was buying something if it was ok to pay with 500€ bills so I could break them in something smaller (they don't make them anymore, but before 2020 they were available). The guy replied: "of course you can pay me with 500€! I wish I could have lots of those!"

For any future trips: the cheapest way to get currency in many countries is typically to use a debit card to take cash out of your account from an Automatic Teller Machine after you arrive. Then if you can manage to go into a bank while it is open, you might be able to get some smaller change. I have had multiple experiences when vendors and taxi drivers didn't take cards and they didn't have change. Of course this won't work in the unlikely chance that you travel to Russia or Belarus, where you have to carry in all the cash you will need for your trip. Can you get a debit card from your bank? I have two checking accounts and a debit card for each one. In case I lose one I still have the other one until I get home and my replacement card arrives.

Oh, wow, thank you all! I was under the impression it would be very difficult to change them out.

We’re visiting Italy soon, and wanted to be prepared. We typically use Amex and Visa, and I know Amex isn’t always accepted. Thank you for easing one more worry from my frantic brain!!

See if you can get a debit card/ATM from your bank before going. But also ask if there are commissions for use overseas.
Debit card/ATM work also in some automatic kiosks that require a PIN (you will have a PIN on a debit card), while they don't always work with US issued credit cards (which generally have no PIN). Also merchants prefer debit cards to credit cards because by law they have to pay lower commissions (I think under 0.2% and even zero for small amounts under 5 or 10 euro). Most Italians are more likely to use debit cards/ATM cards for payments rather than credit cards.

Smartphone payments (google pay, apple pay) work too in most places.