Born in 1824 as the fourth son of the 12th shogun Ieyoshi. Sickly from childhood, he may have suffered from cerebral palsy. He became the 13th shogun in 1853 during the turbulent period following Perry's arrival. Lacking the ability to lead government, actual administration was handled by senior councilors Abe Masahiro and later Ii Naosuke. In 1856, he married Atsuhime (Tensho-in), the adopted daughter of Shimazu Nariakira of Satsuma. With no heir, the succession crisis erupted between the Hitotsubashi faction (supporting Tokugawa Yoshinobu) and the Nanki faction (supporting Tokugawa Yoshifuku of Kishu, later Iemochi). Iesada died suddenly in July 1858, the day after naming Yoshifuku as his successor, at age 35.

Frail and lacking in political acumen, but reportedly had a good relationship with Atsuhime. He was simple and introverted, with a hobby of making castella cake.

A tragic shogun at the center of the succession crisis. After his death, Ii Naosuke's Ansei Purge intensified Bakumatsu politics. Atsuhime protected the inner palace after Iesada's death and contributed to the Tokugawa family's survival.