I feel like this game had a bit of a tipping point for me that came right at the time I beat Hades for the first time. Before I did that, every run felt like a struggle with incremental gains in terms of unlocks, knowledge of the mechanics, progress made, etc. I tried my best to min-max each run, and it was still just barely enough to clear what I'd done previously. Once I got my first victory and realized how much more there was to still unravel, I was kind of discouraged, and wasn't sure I'd stick with it.
I did stick with it, and kind of to my amazement, I suddenly found myself winning virtually every run. I've won 18 of 20 since that first win, with most being fairly comfortable victories, and even the two losses I'd asterisk as runs where I did something experimental/risky knowing it'd make the run a likely loss. And it's not like I stumbled into a single broken strategy or anything; I take whatever weapon gives the bonus darkness/gems, take whichever keepsake needs leveling up, take whichever boons which help clear the fated lists, and so on.
I'm sure that won't last forever as the heat rises higher and higher, and I maybe this type experience won't be had by others. But just wanted to throw it out there as an anecdote for others who might be feeling a bit down about how much post-clear content there is when you're struggling to get even that first victory.