Against the Storm Rogue lite city survival builder with gorgeous art, awesome game mechanics and a fantastic dev team whom have basically built the game in collaboration with the community that’s risen around the game.

The game is definitely not for everyone, but ProsperousUniverse kind of stands alone when it comes to people’s descriptions of niches/genres.

The game is an economy/real-time MMO with no real PvP. “Real-time” not like an RTS but as in “this operation takes many hours or days” and everyone has that same time burden.

It’s a game where planning far outperforms “always online” gameplay, so people end up learning spreadsheet software to optimize everything for themselves.

In addition, the UI is modular like a Bloomberg terminal, so it feels right—you feel like a trader.

Kenshi, or noita are the 2 indie games I can think of

Kenshi is unique in a way that it doesn't give you main character vibes. You're a nobody like mostly everyone else.

The World Ends With You (DS): Asymmetric action RPG where your left hand and right hand are playing different games in parallel, which is deeply connected to the game's themes of individual experience and semiotics. The switch remake unfortunately ditches the core gameplay to make it more widely accessible but the original game is worth getting into.

Duskers - scifi, space ships but with a bit different pov then one would expect

Prosperous Universe - someone already described it here so vouching for it too

I am not sure if it qualifies but Paradise Killer is pretty unique all-around. It may seem walking-simulator-ish but the presentation and the overall game-design are definitely a stand out. You're trying to solve a murder mystery and it's completely up to you as the player to decide when you've gathered enough information to make a conviction. There is practically no hand-holding either which is quite rare for a mystery solving/detective game. I know it might not exactly be what OP asked for but I think the game is worth being recommended more.

Persona - a turn based Pokémon-like RPG fused with a social simulator. Your main way of getting stronger isn't by simply levelling up (although it helps) but by fusing multiple monsters that you catch and spending your limited time available with comrades.

Battlezone '98: One of the first notable RTS/FPS hybrids. You drive hovertanks and you build bases and you command other tanks. Set in a secret live war on the Moon, Mars, and Venus between the USSR and the USA during the cold war.

I don't know how many other games have done this (or if anyone actually cares), but Me And My Shadow. It's a 2D puzzle platformer where you have to record your movements to move the shadow version of you in order to reach the end of each level.

It's a discontinued open source game that can be found on SourceForge and has a couple different level packs available for when you complete the ones already included.

Its retro and really rough around the edges (and QTE heavy) and is more of a life sim than a traditional adventure game, but Shenmue I & II introduced day/night cycles with NPC schedules, has a fun martial arts combat system, and the story is kind of like an 80s martial arts film with a detective kick. There's also gambling, drinking, a little bit of working at the docks, darts, retro arcade games, and some sleuthing to progress the story. Your progress from Shenmue I carries over to II

But again its rough around the edges and sometimes referred to as QTE simulator (or Dock Worker Simulator, as I jokingly call it). But somehow, all these elements blend together well to create a unique game. Not going to be for everyone but I really enjoyed it

Final note: I highly recommend using a controller. I ran into issues with KB+M, especially after remapping keys. It broke some of the QTEs.

Dwarf Fortress mostly doesn't have unique gameplay mechanics or anything; but the Legends viewer certainly is a unique feature, due to how all the systems work together to weave randomly generated stories and history of the world through the entire world generation process. So even though you didn't play the game through all those years, the game still kept track of everything going on while simulating the world creation and you can go through it and see all the battles, conflicts, migrations, rise and fall of civilizations, deaths of monsters, etc.

Very surprised that A blind legend didn't make it here, among all those suggestions.

Death Stranding makes the player think about how to walk over difficult terrain with a large amount of cargo on their back without losing their balance and falling down. Most games allow you to run as far and recklessly as you want without having to worry about falling, so it was interesting to actually have to work at it, at least before you unlock various modes of transportation.

Opus Magnum. It's an optimization puzzle game. You have to assemble mechanical arms and other bits (that grab, swing, rotate, push, and pull) into contraptions that assemble resources that look like molecular diagrams. Optimization puzzles aren't unique but I felt like the pieces you build the contraptions out of in this game are pretty unique, the game is on a hex grid so rotation can play a big roll. Another interesting thing the game does is that to beat a level you simply have to accomplish a proper assembly, which in itself isn't that hard, but the game grades you on three different metrics (speed, size, cost) and gives you no overall score to tell you how much you should value each metric. In this way it is up to your preferences what you want to optimize for if anything. I had fun trying to minmax every stat separately on every level before building my "compromise" machine was not supposed to make big sacrifices in any field.

A lot of people have mentioned it but I definitely recommend Obra Dinn, haven't played a mystery game as unique and enthralling.