Destroy All Humans! Big Willy Unleashed is the third action-adventure game in the series of Destroy All Humans games. The game takes place prior to the events of Destroy All Humans Path of Furon and Destroy All Humans 2. The game was originally to be released on the Nintendo Wii, Sony PSP and Playstation 2, but the PS2 version of the game was canceled due to budget cuts.

Destroy All Humans! Big Willy Unleashed received mixed reviews for its Wii release, most of which were negative. Bland graphics and difficult gameplay were cited by reviews, with its humor being praised.

1. Metacritic: 55%
2. Gamespot: 5.5/10
3. IGN: 5.8/10
4. Ngamer: 51/100
5. Nintendo Power: 7/10
6. Official Nintendo Magazine: 34%
7. Games Master UK: 74/100
8. N-Revolution Magazine: 7.6/10
9. Deeko: 4/10
10. AtomicGamer: 42%
11. GamePro: 2.5/5
12. Videogamer.com: 5/10

Big Willy Unleashed takes place in the 1970s, a decade after the last installment in the series. Cryptosporidium-138 and his mentor Orthopox-13 promote the popularity of Big Willy, a fast food restaurant owned by Pox, where the secret recipe on the menu is human meat. Patty Wurst, a kidnapped heiress working with their restaurant rival Colonel Kluckin, has discovered the secret recipe of the restaurant. Crypto and Pox must stop her before they are exposed.