Jade from Beyond Good and Evil.

Alien Isolation

Returnal.

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.

Ms Pac Man obviously

Surprised no one has mentioned Tomb Raider yet. Others not yet mentioned:

• Assassin's Creed: Liberation, and Chronicles: China
• Beyond: Two Souls
• The Last of Us Part II
• inFamous: First Light

Can I suggest some great novel games?

**VA-11 HALL-A: Cyberpunk Bartender Action **

• play as a bartender and change outcomes of stories by providing different drinks

Fatal Twelve

• death game, mystery, lesbian couple as main character, one of the best

Silent Hill 3 has a great female protagonist imo, but you have to play Silent Hill 1 to get the gist of the story in 3.

I enjoyed Uncharted: The Lost Legacy. It's a bit shorter than U4, but still worth playing. I liked Chloe and Nadine together.

The Last of Us: Part II !

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.

Most games I can think of have been mentioned, but I found Signalis to be an interesting experience assuming you can get past the annoying inventory management

Great list from @mint@beehaw.org, just a few more:
Gris is an absolute gem.
The A Plague Tale duology is also up there (with Requiem being my favourite game of all time, so I'm extremely biased, sorry / not sorry :D).

The Mass Effect series is still my favorite, you can choose your protagonist to be female and the game will adapt accordingly. Or Dragon Age if you are more into fantasy.

Aquaria

A very well put together Metroidvania. The map is very fun to explore, good boss fights, great music, and interesting story.

A group of developers have created a version of the game and it's sequels that runs on modern machines: http://nolfrevival.tk/

Edit: this was meant as a reply to @KIM_JONG_JUICEBOX 's comment. No One Lives Forever is a whip smart spy FPS that nails the Bond aesthetic but stars an unforgettable female protagonist, Kate Archer. Download it for free above.

I really liked the Edna & Harvey games

There's Alien: Isolation if you're looking for a horror game. Every so often I'll go and give it another playthrough. That game was phenomenal, especially if you're a fan of the Alien movies

Not seeing Transistor but if you want a female protagonist that will make you cry your eyes out at the end, I recommend her.

Games As Literature 101 has a documentary that goes into a deep dive about Red as a character.

Also some people used Red's song from Transistor as a wedding song 😃

It's older, but The Longest Journey is good. Unfortunately, the final game in the series kinda sucks.

While it's an ensemble, most people would agree that the main character of Final Fantasy VI is a woman—they just might disagree about which woman is the lead.

I also liked the first Xenosaga game, but again, it's a series that goes pretty badly downhill.

Don't see it mentioned yet, it's an older game but Remember Me is pretty good

Plague Tale:Innocence and Requiem

Night in the Woods is objectively the best game ever made by any measure. Tacoma and Gone Home are amazing too.

I mean I dunno, it depends on what kind of games you like, surely?

Resident Evil Remake 2 and 3, great games with both male and female protagonists!

Whoa whoa whats wrong with Senua?