Depretis was born at Bressana Bottarone, near Stradella, now in the province of Pavia (Lombardy). From early manhood he was a disciple of Giuseppe Mazzini and affiliated with the La Giovine Italia. He took an active part in the Mazzinian conspiracies and was nearly captured by the Austrians while smuggling arms into Milan. Elected deputy in 1848, he joined the Left and founded the journal Il Diritto, but held no official position until appointed governor of Brescia in 1859.
In 1860 he went to Sicily on a mission to reconcile the policy of Cavour (who desired the immediate incorporation of the island in the kingdom of Italy) with that of Giuseppe Garibaldi, who wished to postpone the Sicilian plebiscite until after the liberation of Naples and Rome. Though appointed pro-dictator of Sicily by Garibaldi, during the dictatorial government, he failed in his attempt.
Accepting the portfolio of public works in Urbano Rattazzi's cabinet, in 1862, he served as intermediary in arranging with Garibaldi the expedition that ended disastrously at Aspromonte. Four years later, on the outbreak of war against Austria, he entered the Ricasoli cabinet as minister of navy, and there he insisted with admiral Carlo Persano on the attack against the island of Lissa—as a revenge for the Italian defeat of Custoza. But he also refused to give to admiral Persano detailed orders about the expedition in the Adriatic Sea against the fleet led by Wilhelm von Tegetthoff. His apologists contend, however, that, as an inexperienced civilian, he could not have made sudden changes in naval arrangements without disorganizing the fleet, and that in view of the impending hostilities he was obliged to accept the dispositions of his predecessors.
Upon the death of Rattazzi in 1873, Depretis became leader of the Left. He prepared the advent of his party to power and was called upon to form the first cabinet of the Left in 1876. Prior to this, Depretis "was a journalist-politician who had allied himself in parliament with the Left. When he came into power it was as the leader of the Left, and as such he ruled as Prime Minister, save for a brief interlude, for most of the eleven years from 1876 to 1887." Overthrown by Benedetto Cairoli in March 1878 on the grist-tax question, he succeeded, in the following December, in defeating Cairoli, became again premier, but on July 3, 1879, was once more overturned by Cairoli.
In November 1879 he entered the Cairoli cabinet as minister of the interior, and in May 1881 succeeded to the premiership, retaining that office until his death. During the long interval he recomposed his cabinet four times, first throwing out Giuseppe Zanardelli and Alfredo Baccarini in order to please the Right, and subsequently bestowing portfolios upon Cesare Ricotti-Magnani, Robilant and other Conservatives, so as to complete the political process known as trasformismo. A few weeks before his death he repented of his transformist policy, and again included Francesco Crispi and Zanardelli in his cabinet.
During his long term of office he abolished the grist tax, extended suffrage, completed the railway system, aided Mancini in forming the Triple Alliance, and initiated colonial policy by the occupation of Massawa; but, at the same time, he increased indirect taxation, corrupted the parliamentary parties, and, by extravagance in public works, impaired the stability of Italian finance. He argued that a wider suffrage would give citizens a moral dignity and sense of responsibility.