After attending the Catholic University in Lima, Pérez de Cuéllar joined the foreign ministry in 1940 and the diplomatic service in 1944. After serving in embassies in France, the United Kingdom, Bolivia, and Brazil, he returned in 1961 to the Ministry of Foreign Affairs, where he remained until 1969 (except for a two-year term, 1964–66, as ambassador to Switzerland). After serving as Peru's first ambassador to the Soviet Union (1969–71), he was made Peru's permanent representative to the UN, a post that he held until becoming secretary-general on January 1, 1982, succeeding Kurt Waldheim (Waldheim, Kurt) in that post.

Pérez de Cuéllar repeatedly advocated the use of the UN Security Council for keeping the peace and serving as a forum for negotiations. He was reelected to another five-year term as secretary-general in 1986. In August 1988 Pérez de Cuéllar personally negotiated the cease-fire that ended active hostilities in the Iran-Iraq War.

In 1995 Pérez de Cuéllar ran unsuccessfully against Alberto Fujimori (Fujimori, Alberto) for the Peruvian presidency. He later served as prime minister of Peru (2000–01), helping to restore democracy to the country. A skilled diplomat, Pérez de Cuéllar wrote Manual de derecho diplomático (1964; “Manual of Diplomatic Law”).