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Zoe Saldaña as Joe McNamara, a CIA senior case officer in charge of the Lioness program, who previously served as a Lioness operative responsible for the death of Abu Musab al-Zarqawi.
Laysla De Oliveira as Cruz Manuelos, a Force Recon Marine and Lioness operative in the first season, turned Delta Force operator and Josephina's handler in the second season, and QRF team member in the third season. (Note: Delta is an Army unit; Marines can and have been members of this unit. Later, in season 2, “Joe” alludes to Manuelos being promoted to Sergeant First Class, that is an Army rank - not Marine Corps.)
Dave Annable as Dr. Neal McNamara, Joe's husband and a pediatric oncology surgeon
Jill Wagner as "Bobby", a Ground Branch QRF team leader for the Lioness program.
LaMonica Garrett as "Tucker", a QRF team member and former Marine.
James Jordan as "Two Cups", a QRF team member and former Green Beret.
Austin Hébert as "Randy", a QRF team member.
Jonah Wharton as "Tex", a QRF team member and former Navy SEAL.
Stephanie Nur as Aaliyah Amrohi (season 1), the daughter of a suspected terrorist financier
Hannah Love Lanier as Kate McNamara, the teenage daughter of Joe and Neal
Nicole Kidman as Kaitlyn Meade, a CIA Clandestine Service supervisor and Joe's boss
Morgan Freeman as Edwin Mullins, the U.S. Secretary of State
Thad Luckinbill as Kyle McManus (season 2–present; recurring season 1), a CIA senior case officer and Joe's colleague
Michael Kelly as Byron Westfield (season 2–present); recurring season 1), the CIA's Deputy Director of Operations and Kaitlyn's boss
Genesis Rodriguez as Captain Josephina Carrillo (season 2–present), a U.S. Army Black Hawk pilot recruited into the Lioness program due to her family connection to the Mexican cartel that kidnapped an American congresswoman. In season 2 she joins the QRF team as their pilot.