Born on November 13, 1896, in Yamaguchi-cho (today Yamaguchi City), Yamaguchi Prefecture, the second son of Sato Hidesuke and Moyo. In childhood he was adopted into his father's natal Kishi family. He graduated top of his class from the Faculty of Law, Tokyo Imperial University (1920), and entered the Ministry of Agriculture and Commerce. Distinguishing himself as a commerce-and-industry bureaucrat, in 1936 he was seconded to the government of Manchukuo, where as deputy chief of the industrial department he controlled the Manchukuo economy. He returned in 1939, served as vice-minister of commerce and industry, and in 1941 became minister of commerce and industry in the Tojo Hideki Cabinet, directing the wartime economy. In 1944 he joined the move to bring down the cabinet, triggering the collapse of the Tojo Cabinet. After the defeat he was detained at Sugamo Prison as a suspected Class-A war criminal, but was released without indictment on December 24, 1948. After his purge was lifted, in 1953 he was elected to the House of Representatives from the Liberal Party and returned to politics. In 1955 he was involved in founding the Liberal Democratic Party and became secretary-general. On February 25, 1957, he took office as the 56th prime minister. On January 19, 1960, he signed the new Japan-U.S. Security Treaty in Washington; in May of the same year he forced the treaty's ratification through, but faced massive opposition from the Socialist Party, Zengakuren, and labor unions in the 1960 security treaty struggle, and announced his resignation on July 15, after the treaty took effect on June 23. He died in Tokyo on August 7, 1987, at 90.

A politician who survived prewar, wartime, and postwar eras, earning the nickname 'Showa Monster.' He had a robust will and political power, rising to the premiership after being a war-crime suspect. Quiet and logical, an official-type leader who did not show emotion, he also had a cool determination that would not choose its means for its ends. 'A politician is no good unless he has strong bad luck' was his pet saying. Although pro-American, he made an autonomous constitution his lifelong goal and aimed at a break from the postwar regime.

The 1960 revision of the Security Treaty fixed the framework of Japan's Cold War diplomacy. He then formed the 'Kishi faction / Seiwakai,' in opposition to the conservative mainstream of the LDP, and from the Kishi lineage came many prime ministers — Fukuda Takeo, Abe Shintaro, Mori Yoshiro, Koizumi Junichiro, Abe Shinzo, Fukuda Yasuo, Kishida Fumio — shaping Japanese politics in the 21st century. In particular his grandson Abe Shinzo carried on Kishi's 'departure from the postwar regime,' trying to realize the Kishi line up to the Peace and Security Legislation of 2015 and the constitutional revision debate of 2022. The birthplace of the Kishi-Sato brothers remains in Tabuse, Yamaguchi, known as the 'town of prime ministers' for having produced three prime ministers including Abe Shinzo.