Born in Tosa (now Kochi), Itagaki was one of the central figures in the Meiji restoration. After the establishment of the new Meiji government, he became a councillor of state, but he oppsoed domination of the government by the Choshu and Satsuma clans.

Itagaki, along with Goto Shojiro of Tosa and Eto Shimpei and Soejima Taneomi of the Hizen domain (now Saga Prefecture), organized the Aikoku Koto and in 1874 they submitted to the government the so-called Tosa Memorial (Minsen Giin Setsuritsu Kempakusho), criticizing the government for its arbitrary exercise of power and calling for the establishment of a national assembly. This document marked the beginning of the Freedom and People's Rights Movement (jiyu minken undo), a nationwide movement for popular rights that would occupy a central place in Japanese politics for at least a decade.

In October 1881 Itagaki and others formed Japan's first genuine political party, the Jiyuto (Liberal Party), and he remained one of the pioneers of party politics in Japan. To him is ascribed the quote "Even when Itagaki dies, freedom will not die", which he supposedly said after an assassination attempt on him.