Yeah, an RPG would do the trick probably.

Planescape Torment, duh...

Alright seriously.
The Gold Box.

Thief Gold. Nuff said.

For me it would be Fallout. The very first, the one and only!

Master of Orion. The original. Still the best Sci-Fi 4X out there.

Probably Stardew Valley. ♥

NO! I refuse to keep only one game :P

Outcast.

Jesus, what a question.

I went into this thinking pfffft that's easy... Turns out it's impossible. I went over my catalogue a few times trying to boil it down, and I can't.. I just can't. Don't make me choose :(

Alpha Centauri.

I'd have to go with something with scads of replay value, which turns me towards open-world . Modability is a big plus. The ones on my list (which would change every time you asked me), likely never to be narrowed down to one title:

- Terraria, though I'm not sure there are mods. But dang, you can do a whole lot in that game
- Never played it but I bet Kerbal Space Program offers a lot of replay
- Also haven't yet played Freespace 2 but it sounds like the mods for that one would extend the game for a very long time. And I love space flight games.
- Railroad Tycoon 2 or 3. Not sure which I'd take.

But these last 3 are the ones I'm leaning toward:

- Mount and Blade: Warband.
- Stalker: Call of Pripyat
- Operation Flashpoint. Going to claim the GOTY edition to get the expansions rolled in with it.

The ONE game? You mean Matrix: Path of Neo? :D

Psychonauts

Stalker Call of Pripyat

The "world" in it is so "alive" that I can play it over and over again (particularly with the many fine mods available for it [SGM in particular]) - where mod can be a small thing - like adding sleeping bags - all the way up to major full campaigns including new maps , monsters, NPC's, and locations. They're all just "mods" in their world.

There's plenty of other games I like quite a lot also - but if it really came down to just one single one - that would be it.