Many people from the domain played important roles in events of the late Edo period including Nakahama Manjirō, Sakamoto Ryōma, Yui Mitsue, Gotō Shōjirō, Itagaki Taisuke, Nakae Chōmin, and Takechi Hanpeita.

However, next daimyō Chōsokabe Morichika joined the pro-Toyotomi Western Army at the Battle of Sekigahara in 1600, and was subsequently deprived of his title, and later his life.

[1] The Chōsokabe's former retainers were extremely hostile to the new regime, while Tosa peasants feared increased exploitation under the new lord and many fled across to the neighboring domains.

[2][3][4] In any event, most of the old vassals of the Chōsokabe, who were half-peasants and half-soldiers, were allowed to remain as lower-ranked samurai within the new regime, with retainers of the Yamauchi clan monopolizing the senior position, and with the most senior Yamauchi retainers and clan members assisted to key points within the domain to prepare for rebellions.

Under his successor, Yamauchi Tadayoshi, new rice field development and new industries were promoted, and the clan's finances remained relatively stable until around the middle of the Edo period.

Subsequently, Yamauchi Toyoshige took action against Takechi's "Tosa Kinnō-tō" party and suppressed the Sonnō Jōi movement in the domain.

Initially a strong supporter of the Kōbu gattai movement to join the shogunate with the Imperial House of Japan, he later led the domain into the Satchō Alliance and played a critical role in 1867 in advising Shōgun Tokugawa Yoshinobu to carry out Taisei Hōkan (大政奉還), and to the return of power to the Emperor.