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.

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 Rami Malek and reunites Nolan with actor, writer, and filmmaker Kenneth Branagh.