"It just shows people seem happy to escape to the movies and have a good laugh," said Anne Globe, head of marketing for DreamWorks Animation.
While parents with children were the bulk of the audience, "Madagascar" also drew teens and adults on their own, who made up half the audience on Friday and one-third on Saturday, Globe said.
Premiering in second place with $19.3 million was the Universal Pictures comedy "Role Models," starring Seann William Scott and Paul Rudd as immature adults sentenced to community service as mentors for two misfit youths.
The weekend's other new wide release, the Weinstein Co. music comedy "Soul Men," opened weakly with $5.6 million, despite the lure of Samuel L. Jackson and his late co-stars, Bernie Mac and Isaac Hayes, who died last summer. Jackson and Mac play an estranged singing team on a reunion road trip to a memorial concert.
Mac also was among the voice cast for the "Madagascar" sequel, providing vocals as Zuba, the father of Ben Stiller's Alex the lion.
"Certainly, he just brought a wonderful heart to the role of Zuba. We were just fortunate to have him for that character," Globe said.
The movie also reunites voice stars Chris Rock, David Schwimmer, Jada Pinkett Smith and Sacha Baron Cohen as the animal gang crash lands in an African nature preserve.
Disney's "High School Musical 3: Senior Year," which had been No. 1 the previous two weekends, slipped to third place with $9.3 million, raising its total to $75.7 million.
"Madagascar" and "Role Models" kicked off a big start to Hollywood's holiday season. The top 12 movies took in $128.8 million, up 32 percent from the same weekend last year.
"It's all boding well," said Nikki Rocco, head of distribution for Universal. "We have lots of really good films coming, lots of commercial films. I love the fact that everybody's going to the movies. I love the fact that everybody likes what they're seeing."
The season continues with Sony's James Bond adventure "Quantum of Solace" on Friday, then Summit Entertainment's vampire romance "Twilight" and Disney's animated canine comedy "Bolt" on Nov. 21.
"Quantum of Solace" continued to pull in big audiences overseas with $106.5 million in 60 countries, raising its total to $160.3 million since it began opening internationally Oct. 31.
Hollywood's domestic revenue for the year stands at $7.96 billion, a fraction ahead of the pace in 2007, when the industry took in a record $9.7 billion, according to box-office tracker Media By Numbers.
Factoring in inflation, the number of tickets sold this year trails last year's admissions by 4 percent. But Hollywood has a stronger lineup this time heading into Thanksgiving, so studios could finish the year with a bang.
"Given where we are and the films in the pipeline, we have a huge shot at more than making up for any kind of attendance deficit," said Paul Dergarabedian, president of Media By Numbers. "You wouldn't know there was a recession if you were just looking at the movie industry."
Estimated ticket sales for Friday through Sunday at U.S. and Canadian theaters, according to Media By Numbers LLC. Final figures will be released Monday.
1. "Madagascar: Escape 2 Africa," $63.5 million. 2. "Role Models," $19.3 million. 3. "High School Musical 3: Senior Year," $9.3 million. 4. "Changeling," $7.3 million. 5. "Zack and Miri Make a Porno," $6.5 million. 6. "Soul Men," $5.6 million. 7. "Saw V," $4.2 million. 8. "The Haunting of Molly Hartley," $3.5 million. 9. "The Secret Life of Bees," $3.1 million. 10. "Eagle Eye," $2.6 million.