The picture, which features Hugh Jackman, Kate Winslet, Halle Berry and Richard Gere among its all-star cast, underperformed at the US box office this weekend, taking just $4.8 million.
Movie 43 has also been met with scathing critical reviews, with its Rotten Tomatoes score sitting at a lowly 4%.
Richard Roeper of the Chicago Sun Times dubbed it "the Citizen Kane of awful", while The Telegraph's Robbie Collin wrote of the film: "After watching Peter Farrelly's Movie 43, I was immediately overcome with a sudden rush of emotion: not amusement, anger or even mild irritation, but a profound and faintly tragic sense of pity."
Addressing the comedy's critical reception, producer Farrelly said: "To the critics - Movie 43 is not the end of the world. It's just a $6 million movie where we tried to do something different. Now back off."
He later added: "You always complain that Hollywood never gives you new stuff, and then when you get it, you flip out. Lighten up."
Reports from cinemagoers also suggested that the US and UK versions of Movie 43 are different.
In the UK the film's framing device involves kids trawling the internet to find the mythical 'Movie 43', while the US version sees Dennis Quaid play a mad screenwriter who links each story together.
Movie 43 earned £787,648 from UK cinemas over the weekend, putting it at number seven in the box office rankings.
Watch the trailer for Movie 43 below: