Born in Stella (Province of Savona) as the son of a well to do landowner, Alberto, he studied at a Salesian college in Varazze, and completed his schooling at the "Chiabrera" lyceum (high school) in Savona.

His philosophy teacher was Adelchi Baratono, a reformist socialist who contributed to his approach to Socialism and probably introduced him to the inner circles of the Ligurian labour movements. Pertini obtained a Law degree from the University of Genoa.

Sandro Pertini was against Italy's participation in World War I, but served as a lieutenant and was awarded several medals for bravery. In 1918 he joined the United Socialist Party, PSU, then he settled in Florence where he also graduated in political science with a thesis entitled La Cooperazione ("Cooperation"; 1924). While in the city, Pertini also came into contact with people such as Gaetano Salvemini, the brothers Carlo and Nello Rosselli, and Ernesto Rossi. Pertini was physically beaten by Fascist squads on several occasions, but never lost faith in his ideals.

After the assassination of PSU leader Giacomo Matteotti by Fascists, Pertini became even more committed to the struggle against the totalitarian regime. In 1926, he was sentenced to internment, but managed to go into hiding. Later, together with Carlo Rosselli and Ferruccio Parri, he organized and accompanied the escape to France of Filippo Turati, who was the most prominent figure of the PSU. Pertini remained in the country until 1926 working as a mason. On his return to Italy, he was arrested in Pisa and sentenced to ten years' imprisonment.

In 1935 he was interned on Santo Stefano Island, Ventotene (LT), Pontine Islands, an island in the Tyrrhenian Sea, where he remained through Italy's entry into World War II and until 1943. There he saved the famous diaries of Antonio Gramsci. Although he had begun suffering from severe illness, Pertini never demanded pardon. He was released a month after Benito Mussolini's arrest, and joined the Italian resistance movement against the Nazi German occupiers and Mussolini's new regime - the Italian Social Republic. Arrested by the Germans, he was sentenced to death but freed by a partisan raid. Pertini then travelled north to organize partisan war as an executive member of PSU (alongside Rodolfo Morandi and Lelio Basso).

After 25 April 1945 (the end of the war in Italy) he was elected to the first Parliament of the new Italian Republic (the parliament which created the modern Italian Constitution), the Constituent Assembly or La Costituente. In the postwar era he was a prominent member of the directive board of the Italian Socialist Party (the PSI, which the PSU had rejoined).

In spite of his intransigent attitude toward the Italian Communist Party, Pertini was suspicious of many policies enforced by the PSI. He criticized all forms of colonialism, as well as corruption in the Italian state and within the socialist party, where he kept an independent political position.

He was appointed president of the Italian Chamber of Deputies in 1968, and in 1978 President of the Italian Republic, the highest office in the Republic. As President he succeeded in regaining the public's trust in the State and institutions. During the Brigate Rosse terrorism period of the Anni di piombo, Pertini was a defender of the institutions he represented. His death in Rome was viewed by many as a national tragedy, and he is arguably one of modern Italy's most accomplished politicians. In December 1988 Pertini was the first person to be awarded with the highly regarded Otto Hahn Peace Medal in Gold by the United Nations Association of Germany (Deutsche Gesellschaft für die Vereinten Nationen, DGVN) in Berlin, "for outstanding services to peace and international understanding, especially for his political ethics and practical humanity."