Sanada was born Hiroyuki Shimosawa in Tokyo, Japan. He began training with Sonny Chiba's Japan Action Club. Originally aiming to be an action star, he developed good all-round martial arts ability.
Sanada was first noticed as a serious actor in the movie Mahjong Hourouki directed by Makoto Wada. Wada and Sanada's relationship is similar to that of John Huston and Humphrey Bogart and since then Sanada has acted in every one of Wada's movies. Those works are filled with a sense of humor and nostalgic attachment for classic movies. He has established himself as a character actor who can play many different roles. Some of his most famous movies are: Tasogare Seibei "The Twilight Samurai", Ring, Kaitou Rubi, and The Last Samurai.
Sanada made an appearance in the 2005 Hollywood film The White Countess , and the Chinese film The Promise . He is known internationally more from The Last Samurai, The White Countess and Sunshine .
In 1999 and 2000, he performed with the Royal Shakespeare Company in their production of King Lear. This marked the first time a Japanese actor had performed with the theatrical group, and earned Sanada an Order of the British Empire
Hiroyuki Sanada has often been credited, in his younger days, as either Henry, Harry or Duke Sanada. His martial arts film career led him in contact with Michelle Yeoh, who he later starred with in Sunshine. He also has a long standing friendship with Jackie Chan, but didn't star in a film with him before Rush Hour 3.
Sanada has joined the cast of the ABC show Lost in 2010 during its sixth and final season. He was offered the role without being given a speech; instead he was just told the character's background. He then watched through the entire series before getting a script. 
Sanada has been said to be one of Japan's most respected actors, and is often cast as the quiet, heroic character, as seen in The Twilight Samurai.