The Universal animated sequel took in $82.5 million over the weekend and $142.1 million across the five-day holiday window, according to studio estimates Sunday.
Disney's "The Lone Ranger" came in second place with more than $29 million. The trouncing for Disney was especially painful because of the high cost of the Western movie, which reportedly cost at least $225 million to make.
The funny ladies of "The Heat" took third place in their second weekend, bringing in $25 million.
"Monsters University" took the No. 4 spot with $19.6 million.
Brad Pitt's "World War Z" rounded out the top five with more than $18 million.
1. "Despicable Me 2," $82.5 million. ($88.8 million international).
2. "The Lone Ranger," $29.4 million ($24.3 million international).
3. "The Heat," $25 million ($4.7 million international).
4. "Monsters University," $19.6 million ($29.5 million international).
5. "World War Z," $18.2 million ($45.2 million international).
6. "White House Down," $13.5 million ($6.8 million international).
7. "Man of Steel," $11.4 million ($21.3 million international).
8. "Kevin Hart: Let Me Explain," $10.1 million.
9. "This Is the End," $5.8 million ($900,000 international).
10. "Now You See Me," $2.8 million ($8.5 million international).
The Associated Press contributed to this report.