Manouchian's father was killed in the Armenian Genocide, and his ill mother died soon after. He and his brother were received by an orphanage in French Syria at the end of World War I. In 1925, they left for France, settling in Marseille and then Paris, where Missak Manouchian worked at the Citroën plant. Together with several conationals, Manouchian started a literary magazine dedicated to left-wing ideals and the preservation of Armenian culture in France. After training in woodworking, Manouchian joined the Confédération Générale du Travail (CGT). His association with the French Communist Party meant that his political activities clandestine in 1939, when the Party was outlawed following its refusal to condemn the Molotov-Ribbentrop Pact.
As a foreigner, Manouchian was evacuated from Paris during the Phony War, working in the Rouen area. After the start of German Occupation in June 1940, he returned and resumed his militancy. He was arrested as result of a raid in June 1941, and detained at Compiègne for the following weeks (no charges were brought up against him).
Initially active in the Armenian section of the armed group Main-d'œuvre immigrée ("Immigrant Workforce"; MOI), he became a notable figure in the new group, the FTP-MOI (created and headed by the Bessarabian Jew Boris Holban in 1942). He was, however, quite careless during his first missions, and was not allowed to contribute for a while.
In 1943, he was assigned duties, and soon replaced the insubordinate Holban as military commissioner for the FTP-MOI (while Joseph Epstein was assigned control of the Paris region). The groups under Manouchian carried out almost thirty successful attacks on German occupiers from August to November.
The group was subject to surveillance work of the authorities, and most members had been captured during mid-November: 68 arrests, including those of Epstein and Manouchian - he was captured in Évry, and was for days subject to torture. The infamous piece of Nazi propaganda entitled l'Affiche Rouge ("The Red Poster"), printed in 15,000 copies, depicted him as:
In 1985, his widow Mélinée Manouchian (who had managed to elude Nazi capture) launched a public debate by stating that comrades of the victims had done nothing to prevent their capture and execution.