The animated feature, starring voice work from Adam Sandler and Andy Samberg, opened with weekend sales of $43 million, setting a record for the biggest debut for a September film and the biggest opening for Sony Pictures Animation.
Joseph Gordon-Levitt's science fiction thriller Looper also debuted with strong ticket sales at number two, earning $21.2 million.
Last weekend's top films End of Watch, Trouble with The Curve and House at the End of the Street slipped to round out the top five, while new film Pitch Perfect came in at number six with $5.2 million.
Elsewhere, Finding Nemo (3D) fell three spots to seventh place, while Resident Evil: Retribution also slipped to eighth place.
Won't Back Down, the new Viola Davis and Maggie Gyllenhaal drama, rounds out the list at number ten, debuting with $2.7 million.
The US box office top ten:
1. (-) Hotel Transylvania - $43 million
2. (-) Looper - $21.2 million
3. (1) End of Watch - $8 million
4. (3) Trouble with the Curve - $7.53 million
5. (2) House at the End of The Street - $7.15 million
6. (-) Pitch Perfect - $5.2 million
7. (4) Finding Nemo (3D) - $4.06 million
8. (5) Resident Evil: Retribution - $3 million
9. (7) The Master - $2.75 million
10. (-) Won't Back Down - $2.7 million
Watch a Hotel Transylvania trailer below: