Iesada was born in Edo Castle as Masanosuke (政之助)—the fourth son of the 12th shōgun Tokugawa Ieyoshi with his concubine, known as Honjuin.

Iesada became shōgun on the sudden death of his father, Tokugawa Ieyoshi at the height of the Black Ships episode.

Already in poor health, he took no active role in political affairs, leaving negotiations with the Americans in the hand of Abe Masahiro.

Abe resigned his post shortly afterwards, and was replaced as leader of the rōjū by Hotta Masayoshi.

[2] The earthquake and tsunami also struck Shimoda on Izu peninsula; and because the port had just been designated as the prospective location for a U.S. consulate, some construed the natural disasters as demonstration of the displeasure of the kami.

[4][5] On 18 December 1856, he married Princess Atsu, adopted daughter of Shimazu Nariakira and Konoe Tadahiro.

On 21 October 1857, Iesada received the newly arrived American Consul Townsend Harris in an audience at Edo Castle.

[9] Tokugawa Iesada is featured in the 2008 NHK taiga drama Atsuhime, which chronicles the life of his wife Tenshō-in.

Iesada's portrayal in this series (unlike most other characterizations of him as an imbecile),[10] presents a romanticized (and largely-fictionalized) image him as a reasonable, if weak-willed individual, whose interactions with his wife Atsuhime pushed him to exert effort into his work as shōgun.