He was named Baruh Djaki Karyo at birth in 1953 in Istanbul, Turkey; his mother was Greek Jewish and his father was from a Turkish Jewish family with ancestral roots in Spain (Sephardic Jewish). When he was young, his family moved to Paris, France, where he grew up. The spelling of his name, Djaki, was changed to Tchéky in a form of French transliteration. As a young man, Karyo studied drama at the Cyrano Theatre and later became a member of the Daniel Sorano Company, playing many classical roles.

He was nominated for a César Award for Most Promising Actor for his role in La Balance. In 1986, he was awarded the Jean Gabin Prize in recognition of his acting performances.

Karyo is also a musician and songwriter. In 2006 he released the album Ce lien qui nous unit (English: “The link that binds us”), and released Credo in 2013 on his 60th birthday.

In 2014 and 2016 Karyo appeared as Julien Baptiste in the acclaimed BBC One/Starz drama series The Missing. He has received critical praise for his performance.

In 2018, Karyo appeared as Elisha in Mary Magdalene, written by Helen Edmundson and directed by Garth Davis.

In April 2018, it was confirmed by that Karyo would reprise his role as Julien Baptiste in a spin-off series titled Baptiste, to be written by Jack and Harry Williams. The new six-episode series began on 17 February 2019.