The film, which starts Robert de Niro and Ben Stiller, took $26 million, beating off competition from Joel and Ethan Coen's True Grit, which took slightly less with $24.5 million.
Falling to third place is the Disney sequel Tron: Legacy which took $18 million, followed by family film Yogi Bear at $13 million.
Rounding out the top five films of the weekend is the third film in the Chronicles Of Narnia franchise, which took $10.5 million.
The rest of the box office top ten is filled up with a number of smaller independent films, including The Fighter and Black Swan.
The US box office top ten in full:
1. Little Fockers - $26,300,000
2. True Grit - $24,500,000
3. Tron: Legacy - $18,300,000
4. Yogi Bear - $13,000,000
5. The Chronicles Of Narnia: The Voyage Of The Dawn Treader - $10,500,000
6. Tangled - $10,008,000
7. The Fighter - $10,000,000
8. Gulliver's Travels - $9,100,000
9. Black Swan - $8,500,000
10. The King's Speech - $7,600,000