What do you guys think? Theres so many set during middle ages with knights and swords etc then you have the opposite being sci fi far into the future but are they really that unique in their timeframes?

You also have the historical ones that slightly change the setting and realism (assassins creed) but I really want to know what games you think are the most creative and unique in terms of combining the time period and setting.

The most creative are clearly those that have nothing to do with Earth or its histories or predicted futures. One might consider Star Wars an example, for instance, since it is not related to Earth or our civilizations' timelines ("a long time ago in a galaxy far, far away"), though it does keep a lot of similarities for the sake of relating the audience to the characters and plot.

Games like Spore don't even keep the familiar elements of our civilizations. The "characters" look nothing like us, the "plot" are not the Machiavellian good-vs-evil, etc.

There are games set in less-cliched portions of the world/history such as pre-conquistador Pacific Islander tribes or the like.

There are games where you play as non-human entities, such as a dog or a ghost or an AI.

There are games with less common plots such as Sim City or Pokemon Snap which have nothing to do with fighting but rather with collection. Or games like Mario is Missing! or even Reader Rabbit which are education-oriented. Not to mention romantic sims or the like (really, probably best not to mention those too much...) Or there are sports games that can range from Medieval Games to modern "realistic" games to the fanciful like Mario Kart or Nitronic Rush.

Sticking with purely the standard game formula and human-like characters like you seemed to be asking about, you have games like Secret of Evermore which includes multiple time periods or games like Final Fantasy with a mixture of sci-fi and fantasy in a fabricated universe. Or things like Kingdom Hearts which mixes a variety of fabricated Disney Worlds with those of Final Fantasy.

I think the single least common setting would be non-human/non-earth historical/fantasy, followed by non-human/non-earth futuristic. Both of which I would really enjoy seeing more of. I'm quite tired of settings that are 70% or more similar to some earthly historical period or one of the common visions of the future (e.g. zombie apocalypse) or common visions of historical fantasy (e.g. Tolkien).

I want to see the player as an intelligent nonhuman alien acting within an alien culture which has evolved to fit their alien biology (maybe including egg-laying or an insect-hive-like social structure). I want to see shapeshifters which aren't supernatural and aren't wolf-based. I want to see tribal cultures not directly based on some earthly tribal culture. I want to see "medieval" fantasies where magic-based technology is abundant and the presence of magic has resulted in a society which is really different from medieval europe.

The only somewhat common setting in books that I think hasn't been done enough in video games yet is the humanoid/rider psychically bonded with an intelligent nonhuman, whether in the form of a dragon, a biological spaceship, a personified magical weapon (as in Death Eater and Bleach)m or some other kind of simbiotic partnership between a humanoid and an alien.