Mako was married to actress Shizuko Hoshi with whom he had two daughters (who are both actresses) and three grandchildren.
He was nominated for an Academy Award for Best Supporting Actor for his role in the 1966 film The Sand Pebbles, and for a Tony Award for Best Leading Actor in a Musical for the 1976 musical Pacific Overtures. Other roles include the Chinese contract laborer Mun Ki in the 1970 epic movie The Hawaiians starring Charlton Heston and Tina Chen, the sorcerer Nakano in Highlander III, the Wizard Akiro, opposite Arnold Schwarzenegger, in the two Conan movies Conan the Barbarian and Conan the Destroyer, Kanemitsu in Robocop 3 in 1993, Kungo Tsarong in Seven Years in Tibet, and Admiral Yamamoto in the 2001 film, Pearl Harbor. He also had a role in Bulletproof Monk. In 2005, Mako had a cameo role in Memoirs of a Geisha. Mako's last leading role was in the 2005 film Cages, written and directed by Graham Streeter.
He appeared on the TV show McHale's Navy several times, playing Japanese soldiers. He also later appeared on the TV show M*A*S*H, playing multiple roles such as a Chinese doctor, North Korean soldier, and South Korean major. He was the blind philosopher Li Sung in two episodes of the TV show The Incredible Hulk. Mako also appeared in an episode of the TV show F Troop. He also fought Bruce Lee in an episode of "The Green Hornet". He played Jackie Chan's uncle/Sifu in Chan's first American movie "The Big Brawl". Mako voiced Commander Shima in the video game Medal of Honor: Rising Sun. He also was a guest star in an episode of Monk. His last "made-for-TV" movie appears to be "Rise: Blood Hunter" in 2007.
He was the voice actor of the evil demon Aku in the animated series Samurai Jack, and as the parody of Aku, Achoo, in Duck Dodgers, as well as Iroh in Avatar: The Last Airbender. He had a guest appearance in the Nickelodeon movie Rugrats in Paris: The Movie as the boss of Coco. He guest-starred in the episode "A Good Day" of The West Wing as an economics professor and former rival of President Bartlet.
Mako has a motion picture star on the Hollywood Walk of Fame at 7095 Hollywood Blvd. He was among the actors, producers and directors interviewed in the documentary The Slanted Screen (2006), directed by Jeff Adachi, about the representation of Asian and Asian American men in Hollywood.
During an Avatar: The Last Airbender episode, titled "The Tales of Ba Sing Se", which comprises several small stories about the main characters, there is a segment titled, "The Tale of Iroh". It features a dedication to Mako, as he was the voice actor for the character of Iroh for the first and second season. He was also featured in the Memoriam Montage in the 79th Academy Awards.