Destroy All Humans: Big Willy Unleashed finds Crypto and Pox stuck in 1970's America. After other attempts at world conquest, Pox has decided to take over the world by starting a chain of burger joints called Big Willy's. Of course, not everyone is happy about Pox's willingness to serve humans (think about it...), so heiress Patty Wurst and Colonel Kluckin' have made it their goal to stop Pox's new business venture, making it Crypto's job to make sure Pox succeeds.
Gameplay is similar to past games in nearly every aspect. Crypto is turned loose in an open world city and given missions by Pox. Missions are usually in the "destroy this" or "destroy that" category; though most just seem like a way to fit in as many "Big Willy" jokes in as possible. Past games weren't that great from a gameplay standpoint, but the game's sense of humor was good enough to make up for other shortcomings. Continuing a slide that began with the second game, Big Willy Unleashed isn't nearly as funny and replaced the original's wit with nothing but really bad, overdone sexual innuendo.
Getting back on track, the play area seems like it reduced, so there's little room for exploration. While it is still fun to go on rampages throughout the city, the areas aren't big enough that you can lose yourself. Even rampages aren't as much fun since there are fewer people on the street. When it comes to missions, earlier ones are pretty entertaining, but eventually you're just doing the same thing. Some are also really short or not all that interesting in the first place.
There's also a two-player variant where you and a friend can either compete over beacons or defend a restaurant against increasing numbers of attackers. Neither mode is interesting and feels like it was slapped on just so the game could claim multiplayer functionality.