The game is set in the early 1970's. The game begins with Pox demanding you to harvest more DNA crucial for the Furon Empire at Sin City (a spoof of of Las Vegas, which is nicknamed "Sin City" by some.)
Once Crypto arrives there, he must face off dozens of humans in order to collect their DNA for the next seveteen levels. It's either win, lose or die, as what happens in Sin City, stays in Sin City.
Aside from featuring the usual arsenal from the first few games, Destroy All Humans! Crypto Does Vegas features three new weapons unique to DAH!; the Gloom Gun, which can stun humans with hard bouts of petrifiying depression, Distinegrator grenades (most likely spun-off from the Disintegrator Ray) which when tossed can completely toast their targets and the Plasma Blaster, a gun capabe of evaporating it's targets in a single shot.
- As of 2016, the game has been been removed from mobile app, thus making it lost.
- It is also known as "Destroy All Humans! 3: Crypto Does Vegas" in some areas.