The son of a converted Jewish lawyer (who had taken his sponsors' historic name at baptism), Manin studied law at Padua, graduating at age 17. Early in his practice, he showed little interest in politics and disapproved of the conspiratorial activities of the Carbonari and other revolutionary groups. But in the late 1840s, Manin underwent a change and joined the patriot Niccolò Tommaseo in giving expression to the discontent of the Venetian people under Austrian rule.

When Manin presented a petition for home rule to the Congregation, the quasi-representative body of the Austrian province of Venetia, he was imprisoned along with Tommaseo (January 1848). After the rebellions of the following March, however, he was freed and made president of the Venetian republic, in which capacity he reluctantly accepted the project of union with the kingdom of Piedmont-Sardinia in the name of Italian unification. He led a heroic defense of Venice against an Austrian siege even after the defeat of the Piedmontese army at Novara; when cholera and bombardment finally forced surrender in August 1849, Manin was among those excepted from amnesty and was banished. For the remainder of his life he lived in Paris, where he strove to enlist French sympathy for the Italian cause. In 1868, 11 years after his death, his body was returned to liberated Venice for a state funeral.