Main

• Nonso Anozie as Tommy Jepperd,^[4] a traveler and reformed Last Man who saves Gus from poachers and reluctantly accompanies Gus on his journey to find his mother. Gus refers to him as "Big Man". He was a famous professional football player before the apocalypse.
• Christian Convery as Gus,^[4] a sheltered and naive 10-year-old half-human, half-deer boy who wants to find his mother. Tommy refers to Gus as "Sweet Tooth" due to his obsession with candies.
• Adeel Akhtar as Dr. Aditya Singh,^[5] a doctor who is desperate to find the cure for the disease caused by the H5G9 virus, also known as the Sick, in order to cure his infected wife Rani.
• Stefania LaVie Owen as Bear, the leader and founder of the Animal Army who saves hybrids. It is later revealed that her name is Rebecca "Becky" Walker.
• Dania Ramirez as Aimee Eden,^[5] a former therapist who creates a safe haven for hybrids called The Preserve.
• Aliza Vellani as Rani Singh, Dr. Aditya Singh's wife who has the Sick.
• James Brolin as narrator.
• Will Forte as Pubba (season 1),^[5] Gus' father^[4] who raised him in a secluded cabin in Yellowstone National Park to protect him from the outside world of hatred towards hybrids. It is later revealed that his name is Richard Fox. He was a janitor at Fort Smith Labs in Goss Grove, Colorado.

Recurring

• Sarah Peirse as Dr. Gladys Bell (season 1), a doctor who is dying of cancer and leaves her research of finding a cure for the Sick to Dr. Singh. It is later revealed that she does not have cancer, but is refusing to continue her research, much to General Abbot's dismay.
• Neil Sandilands as General Abbot, the leader of the Last Men, who hunts hybrids. It is later revealed that his first name is Douglas.
• Naledi Murray as Wendy, Aimee's adopted hybrid daughter who is half-pig and half-human. Aimee often refers to her as "Pigtail". She is the biological daughter of Bear's foster parents.

Guest starring

• Amy Seimetz as Birdie, a woman who Gus assumes is his mother. It is later revealed that her first name is Gertrude. She was a geneticist at Fort Smith Labs.