The film, starring Bradley Cooper and Zach Galifianakis, earned $86.5m (£52.5m) over the weekend making it the biggest comedy movie debut ever.
Despite lukewarm reviews, it edged out animated sequel Kung Fu Panda 2, starring Jack Black and Angelina Jolie, into second place.
The Dreamworks film took $48m (£29.1m).
The fourth movie in the Pirates of the Caribbean franchise made $39.3m (£23.8m) in its second week, and took its worldwide box office total to $623.7m (£378.7m) so far.
The comedy Bridesmaids, about a group of women preparing for their wedding day supporting roles, grossed $16m (£9.7m) in its third week of release.
The top five was rounded off by comic-book adventure Thor, directed by Kenneth Branagh, which made $9m (£5.5m).
