It's supposed to be a big day for Doug Billings (JUSTIN BARTHA) and Tracy Garner (SASHA BARRESE). After all, they're to be married in just a few hours, but there's one little hitch. Doug's best friends, teacher Phil Wenneck (BRADLEY COOPER) and dentist Stu Price (ED HELMS), along with Tracy's goofball brother, Alan (ZACH GALIFIANAKIS), seem to have lost the groom.
Having traveled from Los Angeles to Las Vegas for some bachelor party festivities, the foursome apparently partied so hard that they don't remember what happened or know what's come of Doug. The story then rewinds two days when Phil, Stu and Alan regain consciousness the morning after, with Doug missing.
In his place is a tiger in the bathroom, a baby in the closet, and Stu missing a tooth, but with a wedding band on his finger, indicating he's now married to stripper Jade (HEATHER GRAHAM). That's bad news for him, considering his live-in girlfriend, Melissa (RACHEL HARRIS), cuts him no slack.
But they have bigger concerns, what with the repercussions of the drugs that dealer Black Doug (MIKE EPPS) gave Alan and consequently got them in trouble, not only with the law, but also an effeminate but ruthless crime figure, Mr. Chow (KEN JEONG), as well as former boxing champion Mike Tyson (MIKE TYSON) who isn't too pleased with the foursome's previous nighttime outing.
With time running out and only scant memories of what they did, the trio try to find Doug by piecing together what happened on that wild night.