Jabarkan Pemeranan dari Raiders of the Lost Ark

George ingin memerankan aktor yang relatif tidak dikenal yang akan berkomitmen pada trilogi film untuk memerankan Indiana Jones. Mereka yang dipertimbangkan untuk peran antara Bill Murray, Nick Nolte, Steve Martin, Chevy Chase, Tim Matheson, Nick Mancuso, Peter Coyote, Jack Nicholson, Jeff Bridges, dan John Shea. Casting director Mike Fenton favored Bridges but Lucas' wife and frequent collaborator Marcia Lucas preferred Tom Selleck. Selleck was contractually obligated to filming the television series Magnum, P.I. if it were to be made into a full series. Lucas and Spielberg asked the show's studio, CBS, to release him early 10 days early from his contract. Realizing Selleck was in demand, CBS greenlit Magnum P.I., forcing him to drop out and leaving the production with no lead actor only weeks before filming. The actors' strike of 1980 later put the show on hiatus for three months, which would have allowed Selleck to star as Jones.

Steven mengatakan Harrison sempurna untuk peran itu setelah melihat pemeranannya di The Empire Strikes Back; Kanzanjian mengatakan Harrison selalu dipertimbangkan tetapi tidak ditunjuk sebagai pemeran karena dia sudah menjadi aktor terkenal. George was concerned about seeming reliant on Ford by casting him in another film after Star Wars, and he also did not think he would commit to three films. However, Ford thought it would be a fun project and agreed to the deal. He negotiated a seven-figure salary, a percentage of the gross profits, and the option to re-write his dialogue. Ford undertook extensive exercise to enhance his physique and trained for several weeks under stunt coordinator Glenn Randall to use a bullwhip, becoming proficient enough to disarm the Monkey Man (Vic Tablian). Ford had to rehabilitate his wrist to compensate for an old injury. Ford saw the character as an academic first and an adventurer second.

Untuk wanita yang disukai Indiana, Steven menginginkan seseorang yang mirip dengan wanita terkemuka awal abad ke-20 seperti Irene Dunne, Barbara Stanwyck, dan Ann Sheridan, yang menyamai rekan pria mereka. George menginginkan Debra Winger, tetapi dia tidak tertarik, dan Spielberg menginginkan pacarnya Amy Irving, tetapi dia tidak tersedia. They also considered Barbara Hershey and Sean Young. Karen Allen impressed Spielberg with her professionalism during auditions. One of the first things Spielberg asked Allen was "how well do you spit?" Allen developed a backstory for Marion that included her mother's death and her relationship with Jones when she was 15–16, but Spielberg said it belonged in a different movie. Kasdan named Marion after his grandmother-in-law, and took Ravenwood from a Los Angeles street.

René dimaksudkan untuk menjadi penjahat tangguh untuk melawan pahlawan "peminum bir". Spielberg cast Freeman after seeing him in the docudrama Death of a Princess (1980); Freeman's piercing eyes had captivated him. French Singer Jacques Dutronc and Giancarlo Giannini were also considered. Danny DeVito was approached to portray Sallah, described as a skinny,  tall Egyptian like Gunga Din in Gunga Din (1939). DeVito could not participate because of scheduling conflicts with his sitcom Taxi and because his agent wanted too much money. Rhys-Davies was cast based on his performance in the 1980 miniseries Shōgun. Spielberg asked him to play the character as a mix of his Shōgun role and the character John Falstaff. Ronald Lacey was cast as Toht because he reminded Spielberg of the late-actor Peter Lorre. Klaus Kinski was offered the role but chose to appear in the horror film Venom (1981) because it offered more money.