Mark Harmon reprises his role as the older, retired Leroy Jethro Gibbs to narrate the series, while Austin Stowell plays the younger version of the character in the 1990s timeline.

Before Austin Stowell was cast as young Gibbs, Stephen Amell had auditioned for the role.

Several roles are recast versions of characters from the original NCIS series, including Mike Franks (originally Muse Watson, now Kyle Schmid), Vera Strickland (originally Roma Maffia, now Diany Rodriguez), Jackson Gibbs (originally Ralph Waite, now Robert Taylor), Diane Sterling (originally Melinda McGraw, now Kathleen Kenny), Tobias Fornell (originally Joe Spano, now Lucas Dixon), and Dr. Donald 'Ducky' Mallard (originally David McCallum, now Adam Campbell).

Adam Campbell reprises the role of young Ducky Mallard after having already portrayed the character in four episodes of the original NCIS series.

The character Dwayne Pride appears in a guest role, tying the prequel to NCIS: New Orleans, where he was originally played by Scott Bakula as the show's protagonist.

The series is executive produced by Mark Harmon and his son Sean Harmon, who had previously played a younger version of Gibbs in flashback sequences on the original NCIS show.

The show is filmed on a recreated 1990s-era set of Camp Pendleton, built at Fort MacArthur, a former Army installation located in San Pedro.

The announcement of NCIS: Origins led to the cancellation of NCIS: Hawai'i, which caused a number of angered fans to boycott the new prequel series.