The code realize games are pretty good. Also gonna shout out Pretty Princess Party and it's sequel Pretty Princess Magical Garden Island. They're both on the girlier side of things but don't get as much attention as they should.
How about Final Fantasy XIII? The first game has a full sized party, but Lightning is clearly the main character and the focus. Second game costars Lightning's younger sister and a new male character. Third game is just Lighting.
This is a very obscure one, but there is a mod for Freespace 2 called Blue Planet: War in Heaven which has an amazingly well written story and female lead.
Kena was great. There was so much more they could have done with that world and Kena's backstory, but I think it's the #1 best looking game I've ever played.
There's a lot of great recs in here! A few that I don't see posted yet:
Gone Home is a highly atmospheric exploration game where you play as Katie, a girl investigating her family's house after she arrives home and finds it empty. FYI in case you're with me in the "easily frightened" camp: this one can be just a little tense/scary in that "alone in the house at night" kind of way, but it's decidedly not a horror game.
A Short Hike is a(n unsurprisingly) short and sweet little game where you play as Claire, a bird who goes on a little hike/adventure through, essentially, an island nature preserve. One of my go-to "relax and feel good feelings" replays.
Bayonetta was already mentioned, but I'd specifically like to call out Bayonetta Origins: Cereza and the Lost Demon. It's a quite different game from other Bayonetta installments, with creepy-cute fairy tale vibes and somewhat unique controls.
Mirror's Edge is a good one I haven't seen mentioned yet. A bit older by this point but it was a fun one.
Transistor is another great one. The gameplay was fine but the art and sound is incredible.
Trying to find some that haven't been talked about yet:
Echo. It's a fantastic experimental infiltration game with an AI that adapts to your way of playing. The setup is very impressive.
Pathologic: one of the three playable characters (the Changeling). It's a bizarre russian game, with an unique world, and messy gameplay. Can't recommend it enough.
Va11 Hall-A: chill bartending game in a cyberpunk setup.
The Blackwell series: comfy, kind of amateurish point and clicks by Wadjet Eye. I like them very much.
Transistor: weirdest game by Supergiant. You play as a redhead with a talking sword. I don't remember much about it except that it was good.
The Fall: (pushing it a little bit, since the protagonist is an AI, but I've always seen here as female.) Criminally underrated puzzle games, disguised as metroidvanias.
Eliza (by Zachtronics): the only visual novel I enjoyed. It's hard to explain, it's about AI, burnout, whether tech dehumanizes people, and solitaire.
Hedon Duology: for something completely different, it's a slightly kinky retroshooter, with amazon Orcs fighting demons.
It may sound a bit dumb, but it's excellent. Huge levels, interesting worldbuilding, and a gameplay based on exploration, puzzles as well as shooting.
There's probably a ton more, but that's all I can think about at the moment.
A lot of good suggestions here. Remember Me and Mirror's Edge are also good, perhaps not as great some of the truly outstanding ones already posted though. But if you're looking for something with a cyberpunk edge, both will fit the bill nicely.
Same for Valhalla. Which interestingly canonically has a female player character for the vast majority of the game (the "real world"), but a male lead for the shorter Norse mythology parts of the game. There's a lore reason for it. Though the game does let you actually choose whichever gender you want for either part (but it does recommend the canonical choices). The modern day character is also a woman and has been since Origins.
For an older style AC game, AC Syndicate has you play as opposite gender twins in Victorian London. It's one of my favourite AC games. You do have to play as both twins for some length of the game, but a significant amount of the game lets you choose which to play as (and Evie is more fun to play IMO).
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