Marking Scorsese's sixth feature film collaboration with Leonardo DiCaprio and his tenth with Robert DeNiro, the film is based on the true story of the Osage Native American tribe murders in the 1920s after oil was found on their land.
It also marks the eleventh and last time the Goodfellas creator worked alongside musician Robbie Roberston, who died two months before the film was released.
After hitting cinema screens on October 18, Killers of the Flower Moon has earned $23 million from 3,628 North American theatres over the weekend, according to Variety, and a global total of $44 million.
This makes it Scorsese's third-best opening, after Shutter Island ($41 million in 2010) and The Departed ($26.9 million in 2006).
None of the film's stars – including Jesse Plemons, Lily Gladstone, and Brendan Fraser – were able to promote it due to the ongoing SAG-AFTRA strikes.
However, Taylor Swift's Eras film amassed a whopping $31 million from 3,855 venues and has generated $131 million globally, becoming the first of the two titles to pass the $100 million mark.
Adapted from the 2017 novel of the same name by David Grann, the three-and-a-half-hour Killers of the Flower Moon has proved a hit with critics and cinemagoers alike, landing a 92% rating on Rotten Tomatoes and an A- on CinemaScore.
The Wolf Of Wall Street director Scorcese defended the film's epic runtime, imploring people to "give cinema some respect."
"People say it's three hours, but come on, you can sit in front of the TV and watch something for five hours," he told The Hindustan Times.
"Also, there are many people who watch theatre for 3.5 hours. There are real actors on stage, you can't get up and walk around. You give it that respect, give cinema some respect."
Killers of the Flower Moon is in cinemas now.
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