Okay, I'll name some. Bear in mind that "most unique" is not the same as "most fleshed out" (for instance, Mass Effect is well fleshed out, but it's not particuarly unique in its setting, being an amalgamation of sci-fi tropes).
-Ace Combat (in the sense that its "Earth but not quite" setting is fairly unique)
-Anthem (you'll probably roll your eyes, but I'm serious - I can't think of a setting that uses the same tropes as Anthem combined)
-Assassin's Creed (sort of - the whole "secret war/Illuminati" thing is nothing new, but as a series whose main conciet is living memories across time periods to find McGuffins in the present? I'm sure there's something similar, but regardless, the animus thing kind of pushes it into this territory)
-BioShock (both Rapture and Colombia, but mostly the former)
-Call of Duty: Ghosts (how many military settings have South America uniting to invade North America? Not saying that's a plausible plot point, but hey, least it's not Russians again)
-Ecco the Dolphin (name a setting where a dolphin fights against aliens to save the ocean's sea life from being harvested in a time travelling adventure that spans millions of years. Try it!)
-Fallout (eh, sort of? I've never been able to get into Fallout, and post-nuclear apocalypse is hardly unique, but its alternate history/sense of style arguably carries it forward)
-Gears of War (in the sense that Sera is its own world, takes inspiration from Earth, yet very much isn't Earth - really, see what I said about Ace Combat, the same principle applies)
-Metal Gear (bonkers 20th/21st century history that I'm not sure has an equivalant)
-Resistance (alternate 20th century history crossed over with alien invasion seems straight out of Turtledove, but I'd say it earns a spot)
-Xenoblade (without hyperbole, this might be one of the most bonkers settings I've ever seen. EVER.)