The company's first sequel not related to their Toy Story franchise took $68 million, despite the relatively poor critical reception endured by the family film so far.
The Cameron Diaz and Justin Timberlake comedy Bad Teacher opened with a respectable $31 million in second place, followed by last weekend's superhero box-office topper Green Lantern with $18.3 million.
JJ Abrams's monster epic Super 8 follows in fourth place with $12.1 million, followed by Jim Carrey's family comedy Mr. Popper's Penguins, which rounds out the top five with $10.3 million.
Next weekend sees the 3D release of Transformers: Dark of the Moon, which will serve as Michael Bay and Shia LaBeouf's final entry in the Hasbro film franchise.
This week's US box office top ten in full (studio estimates):
1. (-) Cars 2 - $68,000,000
2. (-) Bad Teacher - $31,000,000
3. (1) Green Lantern - $18,350,000
4. (2) Super 8 - $12,100,000
5. (3) Mr. Popper's Penguins - $10,300,000
6. (4) X-Men: First Class - $6,600,000
7. (5) The Hangover Part II - $5,865,000
8. (7) Bridesmaids - $5,372,000
9. (8) Pirates of the Caribbean: On Stranger Tides - $4,700,000
10. (9) Midnight in Paris - $4,480,000
Watch the trailer for Cars 2 below: