Top Gun: Maverick sees him reprise his role as US navy pilot Pete "Maverick" Mitchell from the original 1986 film.
In its first three days in North American theatres, the sequel earned an estimated $124 million (£98m) in ticket sales, Paramount Pictures said Sunday.
Worldwide, that figure is raised to an estimated $248 million (196m)."These results are ridiculously, over-the-top fantastic," said Chris Aronson, Paramount's president of domestic distribution.
"I'm happy for everyone. I'm happy for the company, for Tom, for the filmmakers."
Cruise's previous biggest opening weekend for a movie came in 2005 with War of the Worlds, which raked in $64 million (£50m).
The 59-year-old's second outing as Maverick also had the fourth biggest opening of any film in the Covid-era, behind the best-selling Spider-Man: No Way Home, second-placed Doctor Strange in the Multiverse of Madness and then The Batman.
He was joined by the Duke and Duchess of Cambridge for the new film's UK premiere recently.
The original movie flew high above the competition, topping last Wednesday's weekly UK film chart, as fans - young and old - prepared for the official release of the sequel last Friday.
Becca Monahan, commercial director of the Official Charts Company said it was "fantastic to see Tom Cruise back in the skies again after 36 years".
"That the original Top Gun has made history by getting to number one on the Official Film Chart and that many of those sales were digital downloads is a great achievement," she noted.
Liz Bales, chief executive of the British Association for Screen Entertainment agreed, saying she expects that the sequel "takes cinema audience's breath away on the big screen" - a nod to the original film's Oscar-winning song.
Critics praised the return of Top Gun: Maverick earlier this month, calling it a "barrier-breaking sequel".
The Independent called it "as thrilling as blockbusters get", praising it as a "true legacy sequel".
The Telegraph called it "absurdly exciting" and "unquestionably the best studio action film in years".