The film stars Cillian Murphy as J. Robert Oppenheimer and Emily Blunt as his wife, biologist and botanist Katherine "Kitty" Oppenheimer. Oscar winner Matt Damon portrays General Leslie Groves Jr., director of the Manhattan Project, and Robert Downey, Jr. plays Lewis Strauss, a founding commissioner of the U.S. Atomic Energy Commission.

Academy Award nominee Florence Pugh plays psychiatrist Jean Tatlock, Benny Safdie plays theoretical physicist Edward Teller, Michael Angarano plays Robert Serber and Josh Hartnett plays pioneering American nuclear scientist Ernest Lawrence.

Oppenheimer also stars Oscar winner Rami Malek and reunites Nolan with eight-time Oscar nominated actor, writer and filmmaker Kenneth Branagh.