A black belt in Kyokushin Karate, he initially gained prominence for his roles in Japanese and Hong Kong action films, later establishing himself as a dramatic actor.

He is best known to international audiences for his roles as Ryuji Takayama in Ring (1998) where he played alongside Nanako Matsushima, who was also his co-star in a 1997 television drama A Story of Love.

His role as the Fool in a production of the Shakespeare play King Lear (1999–2000) gave him theatrical attention, and led to his appointment as an Honorary Member of the Order of the British Empire in 2002.

Sanada's appearances in Hollywood films include Sunshine (2007), Speed Racer (2008), The Wolverine, 47 Ronin (both 2013), Minions (2015), Life (2017), Avengers: Endgame (2019), Army of the Dead (2021), as Hanzo Hasashi / Scorpion in Mortal Kombat (2021), in Bullet Train (2022), and John Wick: Chapter 4 (2023).

Sanada gained acclaim for his role in the FX historical drama series Shōgun (2024) as Yoshii Toranaga, the titular character, a fictionalized version of Tokugawa Ieyasu.

[7] In 1984, Sanada starred with Sonny Chiba and Hiroko Yakushimaru in Legend of the Eight Samurai, which became the number one film in Japan, earning ¥2.3 billion, and was later released in foreign language versions.

[citation needed] In 1992, Sanada played Yoshinari, a stockbroker turned yakuza in the comedy film Keisho Sakazuki (Succession), with Ogata Ken.

[13] Sanada appeared in Rush Hour 3 (2007) with Jackie Chan and Chris Tucker, Danny Boyle's Sunshine (2007) as Kaneda,[8] and The City of Your Final Destination (2009), in which he plays Pete, the younger lover of Anthony Hopkins's character Adam Gund.

[15] In 2013, he appeared in 47 Ronin (the first English-language adaptation of the Chushingura legend, Japan's most famous tale of samurai loyalty and revenge) alongside Keanu Reeves,[16] as Shingen Yashida in The Wolverine opposite Hugh Jackman,[17] and as Takashi Nagase in The Railway Man, a story of vengeance and reconciliation co-starring Stellan Skarsgård and Colin Firth.

[18] Sanada was a guest star as Takehaya, a former Japanese Navy officer and legendary pirate captain in post-plague Asia, in the apocalyptic drama series The Last Ship.

[20] That year, he received the Medal of Honor with Purple Ribbon from the Japanese government for his "artistic developments, improvements, and accomplishments"[21] In August 2019, Sanada was cast in the Mortal Kombat reboot as Scorpion.

[25] In 2023, he portrayed Koji Shimazu, manager of the Osaka Continental Hotel, in John Wick: Chapter 4,[26] and was featured in a multi-commercial campaign introducing Mazda CX-90.