The Warner Bros. action tale about a team that sneaks into people's dreams is DiCaprio's biggest opening weekend, topping his previous best of $41.1 million for last winter's "Shutter Island."
"Inception" falls far short of director Christopher Nolan's best, though. Nolan is the man who directed the Batman blockbuster "The Dark Knight," which opened over the same weekend two years ago with a record $158.4 million.
Warner Bros. has carved out a niche with this particular mid-July weekend. The studio followed "The Dark Knight" with a $77.8 million opening for "Harry Potter and the Half-Blood Prince" over the same weekend last year.
"We like this spot. Not to sound superstitious, but stay away from this weekend. I own it," said Dan Fellman, head of distribution for Warner Bros.
The final "Harry Potter" movie debuts on the same weekend next summer. Warner plans to open Nolan's third "Batman" movie over that weekend two years from now, though Fellman said the studio could move it to an earlier date that summer.
Strong reviews helped "Inception," which stars DiCaprio as leader of a team that normally breaks into people's dreams to steal their secrets but now has been hired to do the opposite - plant an idea in a wealthy heir's subconscious.
Slipping to second place with $32.7 million was the previous weekend's No. 1 movie, Steve Carell's animated hit "Despicable Me." The Universal release raised its 10-day total to $118.4 million.
Disney's family adventure "The Sorcerer's Apprentice" was a dud, opening at No. 3 with $17.4 million, lifting its total to $24.5 million since premiering Wednesday.
"It's disappointing to say the least," said Chuck Viane, head of distribution for Disney, which had high hopes for the movie. "I'm perplexed. I have no response, because I honestly don't know what went wrong."
The movie reunites the team behind the hit "National Treasure" movies - Nicolas Cage, producer Jerry Bruckheimer and director Jon Turteltaub - for an action comedy about an ancient wizard training an awkward apprentice (Jay Baruchel) to take down an evil sorceress in modern Manhattan.
Bruckheimer has been a blockbuster producer for Disney with such hits as "The Rock," ''Armageddon" and the "Pirates of the Caribbean" franchise.
But "The Sorcerer's Apprentice" was the summer's second Disney-Bruckheimer production to come up short at the domestic box office, following "Prince of Persia: The Sands of Time," which was unable to crack the $100 million mark.
"Jerry's working on 'Pirates 4' as we speak," Viane said of the Johnny Depp sequel due out next summer. "I'll go to bat with Jerry any day, because his track record is pretty darn good."
With "Inception" and "Despicable Me," the weekend marked a rare instance when two original stories - not sequels, spinoffs or adaptations of comic books, best-sellers or other properties - led the box office.
Hollywood relies on familiar titles such as "Iron Man 2," ''The Twilight Saga: Eclipse" and "Toy Story 3" for most of its big summer releases, though the occasional fresh idea manages to score with audiences.
"We let all of the sequels and popcorn films come out and get the summer rolling, then we come in here with this original concept," Fellman said of "Inception." ''We're in a good place to run now for the rest of the summer."
Estimated ticket sales for Friday through Sunday at U.S. and Canadian theaters, according to Hollywood.com. Final figures will be released Monday.
1. "Inception," $60.4 million.
2. "Despicable Me," $32.7 million.
3. "The Sorcerer's Apprentice," $17.4 million.
4. "The Twilight Saga: Eclipse," $13.5 million.
5. "Toy Story 3," $11.7 million.
6. "Grown Ups," $10 million.
7. "The Last Airbender," $7.5 million.
8. "Predators," $6.8 million.
9. "Knight and Day," $3.7 million.
10. "The Karate Kid," $2.2 million.