I don't know how well it will work for those with absolutely no familiarity with video games, but a lot of the jokes are pretty accessible if you're familiar with things like Pac-Man, Street Fighter and Mario Kart. And when the plot progresses to the "Sugar Rush" game there's a fair bit of confectionary based humor as well.
It's notable that amongst all the cross-licensing deals Disney worked out, Nintendo characters were not included, at least as speaking parts. Bowser, Peach, and Daisy get non-speaking rolls (though only Bowser is featured prominently) and Mario gets a shout-out, so i guess they worked out a partial deal or something? In some ways that's kind of good, if they'd started tossing Mario and Link and Samus and co around they might have overpowered the other classic characters a bit.
Some non-spoilery highlights:
There's a sweet and awesome short at the beginning, presumably due to the influence of Pixar.
The credits are awesome, and feature a new Owl City song and a song by some J-pop band called "AKB48" which i guess is a big deal in Japan right now.
There is a cute post-credits bit, though it's only a couple seconds long.
And although i didn't realize it at the time, Alan Tudyk is the voice of King Candy.
So anyways, anyone who knows anything at all about video games should definitely go see it, and possibly the rest of you should too.
And if you don't think it's a spoiler, here's the video for the Owl City song from the credits: http://www.youtube.com/watch?v=qM1YMeDsc-M
(The video does contain some clips from the movie, but don't really show anything that hasn't been in the trailers i don't think.)