The film gave another boost to the massive Simpsons licensing programme when it took $72m (£36m) between Friday and Sunday.
It knocked last week's US number one, the Adam Sandler comedy I Now Pronounce You Chuck and Larry, into second place while Harry Potter and the Order of the Phoenix fell to number three.
The film cost a reported $75m (£37m) to make. Once foreign box office receipts are added to the US tally it is expected to have turned a profit in its first week.
US BOX OFFICE
1. The Simpsons' Movie ($71.9m)
2. I Now Pronounce You Chuck and Larry ($19.1m)
3. Harry Potter and the Order of the Phoenix ($12.5m)
4. Hairspray (above, $15.6m)
5. No Reservations ($11.8m)
6. Transformers ($11.5m)
7. Ratatouille ($7.2m)
8. Live Free or Die Hard ($5.4m)
9. I Know Who Killed Me ($3.4m)
10. Who's Your Caddy? ($2.9m)
Source: Media By Numbers