Luigi Longo was born in Fubine, in the province of Alessandria, Piedmont. As a student at the Politecnico di Torino, he became active in the youth wing of the Italian Socialist Party, and engaged in political propaganda from a Marxist perspective. He was a regular visitor to the offices of L'Ordine Nuovo, the newspaper founded by Antonio Gramsci, and became acquainted with Gramsci and Palmiro Togliatti. In 1921, at the Livorno Congress of the PSI, he was one of the instigators of the split in the party, when supporters of Vladimir Lenin's Bolshevik line left to form the Italian Communist Party. He became a leading figure in the new PCI along with Togliatti, Gramsci and others. Longo was a fervent anti-fascist, and, when Benito Mussolini established his Fascist regime in Italy in 1922, he emigrated to France where he became one of the principal leaders of the PCI. In the same year he was a member of a delegation to the Comintern Congress in Moscow, where he met Lenin. He would return to Moscow several times in the years to come, with a specific expertise in political ideology, and was to meet Joseph Stalin and other members of the Soviet Union leadership. In 1933 he became a member of the Comintern's political commission. In 1934 he signed a joint action agreement between the PCI and the PSI.
After the war he was a member of the National Congress and in 1946 was elected to the Constituent Assembly. He was subsequently elected, and repeatedly re-elected, to the Italian Chamber of Deputies on the PCI list and was a member of the party leadership. In 1964, after the death of Palmiro Togliatti, he became secretary of the PCI, declaring that he was "a secretary, not a boss". In this role, he continued Togliatti's line, known as the "Italian road to Socialism", playing down the alliance between the Italian Communist Party and the Soviet Union. He reacted without hostility to the new left movements that sprung up in 1968 and, among the leaders of the PCI, was one of those most disposed to engage with the new activists, although he did not condone their excesses. In late 1968 Longo suffered astroke; although he partially recovered in the subsequent months, from February 1969 he was assisted in most decisions by Enrico Berlinguer acting as vice-secretary. In 1972 Longo resigned the position of party secretary, supporting the choice of Berlinguer as his successor. From that year until his death, eight years later in Rome, he was honorary president of the PCI. In that capacity, he expressed his opposition to the "national solidarity" line the PCI was later to espouse. Longo was also a prolific writer.