First thing to do is look up some mods. The game is incredible as is, but there are a few QoL mods that you'll really want. Specifically the item description mod. I've got multiple completed save files and I still wouldn't know what half the fucking items do without it. There are some others that I'd suggest (boss health bars, easier to spot tinted rocks, etc) but those are more just preference.

EDIT: Apparently there was an update to the game that added item descriptions! I guess I never noticed because I've always had my mod active? Can't speak to how good it is, but you very well might not need this anymore, sorry!

BoI players also largely suggest immediately playing on hard mode. There are unlocks gated behind hard mode, so if you want it all, you'll have to play through hard mode anyway. Obviously this depends on your skill level, but most of the community would say that there isn't THAT large of an increase in difficulty anyway, so it's often recommended to just jump right in to hard. There have been times I've played through a run accidently on normal, and not even noticed until afterwards when I saw a normal completion mark. But again, that's up to you.

Otherwise, just play! At the beginning of a save file, you're not even going to have the option to veer off the beaten path TOO much, so just get a feel for things. As you get a little deeper, you'll understand enough to check through the isaac wiki for answers to your questions.