She was born to a lower-middle-class family, acquired the name Isabel (her saint's name) on her Roman Catholic confirmation, and adopted the name when she became a dancer. She met Perón in either 1955 or 1956 and, giving up her career in show business, became his personal secretary, accompanying him in exile to Madrid, where they were married in 1961. She visited Argentina several times in the 1960s and early '70s, building support for Perón. When Perón finally returned to Argentina to run for president in 1973, Isabel was chosen as his running mate on the suggestion of Perón's close adviser José López Rega. Perón's illness several times elevated her to the position of acting president, and when he died on July 1, 1974, she succeeded him in office, becoming the world's first woman president.

Her regime inherited problems of inflation, labour unrest, and political violence. She attempted to solve the problems by appointing new Cabinet ministers, printing money to pay foreign debts, and imposing a state of siege in November 1974 as the country was on the brink of anarchy. The controversy surrounding her social-welfare minister López Rega, who was forced into exile for graft and terrorist activities, did not help her situation. Moderate military officers urged her to resign, but she stubbornly refused; the economic and political situation continued to worsen, and on March 24, 1976, she was seized by air force officers and held under house arrest for five years. In 1981 she was convicted of corrupt practices, but she was paroled in the summer of that year and went into exile in Spain. Pardoned in late 1983, she submitted her resignation as head of the Partido Justicialista, the Peronist party, from her home in Madrid in 1985. In 2007 an Argentine judge issued a warrant for her arrest on charges of allowing the armed forces to commit human rights abuses during her presidency.