He is known for his roles as Simon Adebisi in Oz, Mr. Eko in Lost, Lock-Nah in The Mummy Returns, Nykwana Wombosi in The Bourne Identity, Heavy Duty in G.I.

[4] Akinnuoye-Agbaje's feature directorial debut, Farming,[5] wrapped production in 2017[6] and had its world premiere at the 2018 Toronto International Film Festival.

After enduring repeated physical attacks by local skinheads, he earned their respect by standing up to them and eventually aligned forces with them.

[9] His best-known acting roles have been as the imposing convict Simon Adebisi in the 1990s HBO prison series Oz and as Mr. Eko on ABC's survivor drama Lost.

[9] Film roles include The Bourne Identity, in which he played a deposed African dictator, Hitu the police officer in Ace Ventura: When Nature Calls, Lock-Nah in The Mummy Returns, and Heavy Duty in G.I.

In May 2017, he announced that casting on the film had begun with Damson Idris in the lead role as Enitan, Kate Beckinsale playing his abusive, neglectful foster mother and Gugu Mbatha-Raw as his teacher and mentor.

[8][17] In 2021, Akinnuoye-Agbaje narrated an immersive audiovisual tour for the Roman Colosseum written by Simon Scarrow for the BARDEUM mobile app.

[20] Akinnuoye-Agbaje asked to be written off Lost, citing a desire to return to London after his foster parents' deaths and to direct a film there.