It will be the first time the veteran filmmaker presents a new film at the festival since he won best director there in 1986 for "After Hours".
Scorsese won the top Palme d'Or prize in 1976 for "Taxi Driver" and also presided over the jury in 1998.
"The Cannes Festival is overjoyed to welcome Martin Scorsese this May on the Croisette, to climb the steps of the Palais des Festivals," the organisers said in a statement.
The film, also starring Robert De Niro, was produced by Apple, which has agreed to release it in cinemas in October prior to streaming on its platform.
Cannes only allows films to compete for the Palme d'Or if they get a theatrical release, which has notably prevented Netflix from entering its films.
"Killers of the Flower Moon" tracks the true story of serial murders of a Native American tribe in an oil-rich part of the United States in the 1920s.