The film boasts an ensemble cast including Matt Damon, Gwyneth Paltrow, Jude Law and Kate Winslet, as the characters battle to save the world from a dangerous virus.
Tate Tyler's comedy-drama The Help falls to second place, after three weeks at the top, with $8.7m, followed by Tom Hardy-led fighting drama Warrior with $5.6m.
John Madden's remake of The Debt, starring Helen Mirren, falls to fourth place with $4.9m, while Colombiana rounds out the top five films of the weekend with $4m.
Next weekend sees the release of Nicolas Winding Refn's Drive, starring Ryan Gosling and Carey Mulligan.
This week's US box office top ten in full (studio estimates):
1. (-) Contagion - $23,135,000
2. (1) The Help - $8,691,000
3. (-) Warrior - $5,607,000
4. (2) The Debt - $4,905,000
5. (6) Colombiana - $4,000,000
6. (5) Rise of the Planet of the Apes - $3,875,000
7. (4) Shark Night 3D - $3,533,000
8. (3) Apollo 18 - $2,913,000
9. (7) Our Idiot Brother - $2,761,000
10. (9) Spy Kids: All the Time in the World - $2,500,000
Watch the trailer for Contagion below: