Tokugawa Iemitsu died in early 1651, at the age of forty-seven. After his death, the Tokugawa dynasty was at major risk. Ietsuna, the heir, was only ten years old. Nonetheless, despite his age, Minamoto no Ietsuna became shogun in Kei'an 4 (1651). Until he came of age, five regents were to rule in his place, but Shogun Ietsuna nevertheless assumed a role as formal head of the bakufu bureaucracy.

The first thing that Shogun Ietsuna and the regency had to address was the rōnin (masterless samurai). During the reign of Shogun Iemitsu, two samurai, Yui Shōsetsu and Marubashi Chūya, had been planning an uprising in which the city of Edo would be burned to the ground and, amidst the confusion, Edo Castle would be raided and the shōgun, other members of the Tokugawa and high officials would be executed. Similar occurrences would happen in Kyoto and Osaka. Shosetsu was himself of humble birth and he saw Toyotomi Hideyoshi as his idol. Nonetheless, the plan was discovered after the death of Iemitsu, and Ietsuna's regents were brutal in suppressing the rebellion, which came to be known as the Keian Uprising or the "Tosa Conspiracy". Chuya was brutally executed along with his family and Shosetsu's family. Shosetsu chose to commit seppuku rather than being captured.

In 1652, about 800 rōnin led a small disturbance on Sado Island, and this was also brutally suppressed. But for the most part, the remainder of Ietsuna's rule was not disturbed anymore by the rōnin as the government became more civilian-oriented. Though Ietsuna proved to be an able leader, affairs were largely controlled by the regents his father had appointed, even after Ietsuna was declared old enough to rule in his own right.