His father, Kyriakos Venizélos, was a Cretan revolutionary who had been deported by Turkey (Crete being then a part of the Ottoman Empire) to the island of Síros for 19 years. At the age of two Eleuthérios left his native village to go to Síros with his family, who had been deported there for a second time after an insurrection against the Ottoman sultan in 1866. Eventually he went to Athens, where he graduated from the Athens University law school.

As leader of the Cretan students in his last year at the university, Venizélos first attracted public attention with his vivid interview of the British statesman Joseph Chamberlain, during his visit to Athens in 1886. On returning to Crete, Venizélos became a lawyer, a journalist, and, a year later, a member of the island's National Assembly and leader of the local parliament's newly formed Liberal Party. During the 1897 Greco-Turkish War, with the support of an army under Colonel Timóleon Vássos, dispatched from Greece, he led an unsuccessful insurrection in Cape Akrotírion, near Khaniá, to secure the union of Crete with Greece. After the intervention of the European great powers, however, Crete's government became autonomous, under the suzerainty of the sultan. When Prince George, second son of King George I of Greece, was made high commissioner of the great European powers in autonomous Crete, Venizélos, at the age of 35, was appointed his minister of justice (1899–1901). He was soon in conflict with the absolutist prince George, however, and, four years later, organized an armed insurrection against his rule, forcing him to leave Crete. Under the new high commissioner, Aléxandros Zaímis, a former premier of Greece, Venizélos again became a member of the Cretan government.

In Greece, meanwhile, a group known as the Military League had formed a revolutionary movement and invited Venizélos to Athens to lead it. Venizélos persuaded the league and King George to revise the Greek constitution. In the elections held in August 1910 Venizélos won a seat as a deputy from Athens. In October he became prime minister, embarking immediately on a program of reform. He reorganized the armed forces, created an alliance of the Balkan Christian peoples (Balkan League), and, in the ensuing Balkan Wars of 1912–13, contributed to the final expulsion of the Ottoman Empire from the Balkan Peninsula. Greece, under his premiership, doubled its territory and population by the acquisition of southern Macedonia (Salonika and the hinterland), south Ípiros (Ioánnina Préveza and Árta), Crete, and the Aegean Islands.

At the outbreak of World War I, Prime Minister Venizélos proposed that the Greek army fight the Turks, who were allies of Germany. King Constantine (Constantine I), however, was in sympathy with the Central Powers and opposed him. For two years Venizélos struggled to change the king's mind, but, after the invasion of Greek Macedonia by German-Austrian-Bulgarian armies (1916), he assumed the leadership of an anti-Constantine insurrection in Macedonia, Crete, and the islands. He organized a new panhellenic army in the Macedonian allied front and, following Franco-British intervention, forced Constantine into exile (1917). Greece, reunited under King Alexander, second son of Constantine, and Prime Minister Venizélos, declared war against the Central Powers.

As soon as hostilities ended, Venizélos went to Paris to participate in the peace conferences. During his absence from Greece for almost two years, he acquired a reputation as an international statesman of considerable stature. In July 1919 he reached agreement with the Italians on the cession of the Dodecanese and secured an extension of the Greek area of occupation in Anatolia. The Treaty of Neuilly with Bulgaria (November 1919) and the Treaty of Sèvres with Turkey (August 1920) were triumphs both for Venizélos and for Greece.

Venizélos returned to Athens in September 1920, and King Alexander suddenly died in October. Despite Venizélos' international triumph, the Greek people, in the November 1920 elections, gave a parliamentary majority to a coalition of monarchist parties, and King Constantine was recalled by a plebiscite. The defeat may perhaps be attributed to Venizélos' loss of popularity during his long absence, the continued maintenance of martial law, and the continuing hostilities with Turkey, the government of which was holding out against the impositions of the Treaty of Sèvres. Venizélos abruptly left Greece and exiled himself in Paris.

Following the defeat of the royal army by the Turks (1922) and the subsequent armed insurrection, led by General Nikólaos Plastíras and General Stilianos Gonatas, King Constantine was dethroned (and succeeded by his eldest son, George), and six royalist leaders were executed. Venizélos assumed the leadership of the Greek delegation that negotiated the peace treaty of Lausanne (1923) with the Turks. Within a few months, another insurrection, led by General Ioannis Metaxas, forced George into exile, and Venizélos returned to Greece to become premier again. He fell into disagreement, however, with some Republican leaders who wished to abolish the monarchy, and he exiled himself again (1924). During the second Hellenic Republic (1924–35) he returned to Greece and reassumed leadership of the Liberal Party. In the general election of 1928, he obtained a huge majority, forming his third, and last, four-year cabinet. During this period Venizélos succeeded in restoring normal relations with all of Greece's Balkan neighbours. His domestic position was weakened, however, by the effects of the Great Depression in the early 1930s; and in the elections of 1932 he was defeated.

After his defeat he continued to lead the Liberals, but the end of his political career came in March 1935, when, after the failure of an attempt to prevent the restoration of the monarchy, he went to Paris, where he died in 1936.