The movie took $77 million, which is more than five times the earnings of its closest rival, action comedy Hot Pursuit.
Hot Pursuit, which stars Reese Witherspoon and Sofia Vergara, made $13.3 million to take second place.
The Avengers sequel has now taken $313 million in just 10 days in the US.
It is the joint second fastest film to pass $300 million, tying with The Dark Knight.
The first movie in the Avengers series, which features Hulk, Iron Man, Captain America and Black Widow, reached that mark in just nine days in 2012.
Warner Bros admitted Hot Pursuit‘s opening weekend total was “a little lighter” than it had hoped, with the studio having estimated takings of $18 million or higher.
That should all change next week though, when Mad Max: Fury Road and Pitch Perfect 2 open.
Blake Lively’s fantasy drama The Age of Adaline was this weekend’s third placed movie with takings of $5.6 million, while Furious 7 took $5.2 million in 4th place.
Furious 7, starring Vin Diesel and the late Paul Walker, has earned $1.5 billion globally to date.
Paul Blart: Mall Cop 2 completed the top five with takings of just under $5.2 million.
North American box office Top 5:
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