He was the son of a poor worker, Tănase Gheorghiu, and his wife Ana. Gheorghiu-Dej joined the Communist Party of Romania in 1930. A railway electrician by trade, he was arrested for taking part in the Griviţa Strike of 1933 and sentenced to prison in the same year, serving time in Doftana and other facilities. In 1936 he was elected to the party's Central Committee and became leader of the prison faction of the party (party members who were incarcerated, a term distinguishing them from party members living in exile in the Soviet Union). As a known activist, he was detained at Târgu Jiu camp during Ion Antonescu's regime and the larger part of World War II, managing to escape in August 1944. He became general secretary in 1944 after the Soviet occupation but did not consolidate his power until 1952 when he purged Ana Pauker and the Muscovite faction from the party. Pauker had been the unofficial leader of the Party since the end of the war.

In 1946-1947, he was a member of Romania's Gheorghe Tătărescu-led delegation to the Paris Peace Conference.

Soviet influence in Romania under Joseph Stalin nonetheless favored Gheorghiu-Dej, largely seen as a local leader with strong Stalinist principles. The economical influence of the Soviet Union was highlighted by the creation of SovRom companies, which directed Romania's commercial exchanges towards unprofitable markets.

On the political level, all of the Romanian political changes had to be pre-approved by Stalin. Gheorghiu-Dej maneuvered Antisemitic trends in the latter stages of Stalinism, by obtaining permission to purge the Party of its "cosmopolitan" leadership, profiting of the Soviet grip on the Securitate. The move mirrored the Prague Trials and the so-called Soviet Doctors' plot. Gheorghe Gheorghiu-Dej was not, however, an anti-Semite himself: most of the purged politicians were Jewish by default (including Ana Pauker), and Gheorghiu-Dej's team always comprised Jews such as Gheorghe Gaston Marin. He was mainly keen on gaining control of Romanian politics, and exhibited more nationalist attitudes.

Up until Stalin's death, Gheorghiu-Dej did not amend repression policies aimed at Romanian society as a whole (such as the works employing penal labor on the Danube-Black Sea Canal - a Stalinist Gulag-type decision which he had countersigned). At the same time, he was the main instigator of the assassination of Ştefan Foriş in 1946 and the arrest of Lucreţiu Pătrăşcanu in 1948 - both of whom had been rivals within the Party. The latter move shows the limitations of Gheorghiu-Dej's nationalism: Pătrăşcanu, as the main figure in the secretariat faction, had been seen as a leading nationalist.

Gheorghiu-Dej was unsettled by Nikita Khrushchev's reforms and the process of De-Stalinization. He became the architect of Romania's semi-autonomous foreign and economic policy within the Warsaw Pact and the Comecon in the late 1950s, notably by initiating the creation of a heavy industry which went against Soviet directions for the Eastern Bloc as a whole (the new large-scale steel plant in Galaţi was a burden on Romanian economy, as it relied on iron resources imported from India and Australia). In fact, Gheorghiu-Dej kept the façade of Stalinism, this time used to point out flaws in the Soviet leadership. While 1954 was the year many political prisoners were released, he organized a new wave of arrests and purges. Adding to the many contradictions of his rule, many of the survivors were released while he was still in power (around 1964). The Securitate was still his instrument of choice, and Romania joined the wave of repression after the 1956 Hungarian Revolution - for example, Hungarian leader Imre Nagy was imprisoned on Romanian soil. Indeed, Romania under Gheorghiu-Dej has commonly been viewed as one of the most loyal of Soviet allies in 1956. Amidst the international attention Gheorghiu-Dej's successor, Nicolae Ceauşescu, attracted for his flashy defiance of Moscow, there is a tendency to forget who made Romania's greater independence vis-a-vis Moscow possible.

The ideological steps undertaken were made clear by the ousting of the SovRoms, together with the toning down of Soviet-Romanian common cultural ventures. In 1958, the Red Army withdrew its last troops from Romania, and the Romanian government began approving the issuing of documents that encouraged anti-Soviet sentiments. The official History of Romania made reference to a Romanian Bessarabia, as well as other topics which tensed relations between the two communist countries. Moreover, the final years of the regime saw the publishing of Karl Marx texts which had previously been kept secret, dealing with Russia's imperial policy in previously Romanian regions that were still part of the Soviet Union.

In his late years, Gheorghiu-Dej established diplomatic relations with the Capitalist World, including the United States. Such steps were highly encouraged by the US government and president Lyndon B. Johnson, who had come to see Romania as a friendly communist country in the Cold War context (1963). Gheorghiu-Dej's right hand was Gaston Marin, vice-president of the government, who renewed US-Romanian political and economic relations. Marin was the last Gheorghiu-Dej supporter to be purged from the Romanian government in 1982 by Nicolae Ceauşescu, and later emigrated to Israel.

Post-World War II and into the early years of Gheorghiu-Dej’s rule, Romania’s relations with the West were tense, marked by accusations of United States espionage and Romanian human rights violations. There were also low levels of trade between Romania and the West as Romania tied itself to the Soviet Union and the other satellite nations; in 1950, Romania’s economic plan involved 89% of trade to be solely with the Soviet Bloc. However, under Gheorghiu-Dej Romania’s willingness to trade with the West became more apparent. For example, 1952 saw the first publication of the journal Romanian Foreign Trade, which offered opportunities to Western traders to buy Romanian goods such as petroleum and grain. Western publications also recognized the potential for Romania to sell its products on the world market; an article from The Times of August 29, 1953, wrote: “[Romania] could, for instance, it is thought, obtain higher prices on the world market for much of what she is forced to export to Russia, foodstuffs included, in return for machinery and aid.” As Gheorghiu-Dej realized, if Romania were able to trade with the West the standard of living would likely rise. From 1953, the West gradually relaxed their export controls, which had limited the products that the U.S., Great Britain, and France could export to Eastern Europe. Gheorghiu-Dej, eager to establish interaction between Romania and the West, relaxed travel restraints on Western diplomats in Bucharest and allowed Western journalists more access to Romania. In early 1954, Romania also appealed to Great Britain about having talks to resolve Romania’s outstanding claims, to which Great Britain agreed in December of that year.

The foreign policy of Romania towards the West was closely tied to its policy toward the Soviet Union; Romania could only develop trading with the West if it asserted its independence from the intensely anti-West Soviet Union. Gheorghiu-Dej realized this, and thus emphasized Romania’s sovereignty. In the Second Party Congress which opened on December 23, 1955, Gheorghiu-Dej gave a five-hour speech in which he stressed the idea of national communism and Romania’s right to follow its own interests rather than be forced to follow another’s (referring to the Soviet Union). Gheorghiu-Dej also discussed opening up trade with the West. In an attempt to increase the dialogue between Romania and the West, in 1956 Gheorghiu-Dej appointed as the Romanian Minister to the U.S. Silviu Brucan, who in April met with both Secretary of State John Foster Dulles and then with President Dwight D. Eisenhower. As a result of these meetings, the U.S. Department of State expressed interest in increasing the interaction between the two nations, including possibly establishing a library in Bucharest.

Romania’s interaction with the West temporarily decreased, however, with the 1956 Hungarian Revolution and the violent response of the Soviet Union to the uprising. Meanwhile, Gheorghiu-Dej continued strengthening the independence of Romania from the Soviet Union. For example, Romanian schools dropped the Russian language requirement. And Romania endorsed the Moscow Declaration of 1957 which stated that "Socialist countries base their relations on the principles of complete equality, respect for territorial integrity, state independence and sovereignty, and non-interference in one another’s affairs…The socialist states also advocate the general expansion of economic and cultural relations with all other countries…” These statements coincided with Gheorghiu-Dej’s claims to national sovereignty and independence. In fact, by 1957 Romania had substantially increased its Western trade; in that year trade with the West had increased to 25% of Romania’s total trade, although little of that included the U.S. By the early 1960s, Romania under Gheorghiu-Dej was more industrialized and productive. After WWII 80% of the population had worked in agriculture, but by 1963 only 65% did. And despite the decrease in hands working the land, agricultural productivity had actually increased. Additionally, Gheorghiu-Dej had successfully begun a strong shift in trade towards the West, further separating it from the Soviet Union; Romania imported much of its industrial equipment from West Germany, Great Britain, and France. This trade pattern followed Gheorghiu-Dej’s economic plan, which he made clear to Great Britain and France in 1960, when he sent his head of foreign intelligence to Paris and London in order to clarify Romania’s desire to interact with the West and disregard Comecon orders. Then by 1964, Gheorghiu-Dej had made a trading agreement with the U.S. that allowed Romania to buy industrial products from them. The agreement came as a result of U.S. businesses’ complaints that they were losing money to Western Europe. During his presidency, President John F. Kennedy, concerned with these businesses’ losses, used his discretionary power to increase trade between the U.S. and Eastern Europe, a policy which President Lyndon B. Johnson also followed.

Throughout this period from the late 1950s to the mid-1960s, Gheorghiu-Dej greatly increased trade with the West, making Romania the first Soviet Bloc country to trade with the West completely independently. Through his policy of national sovereignty, Gheorghiu-Dej increased the popularity of Romania in the West; national U.S. publications moved away from reports in the early 1950s of human rights abuses and oppression, towards articles from the mid-1950s to the early 1960s of Romanian de-satellization. In the early 1960s, The Times also reported often on Gheorghiu-Dej’s and Romania’s increased economic ties with the West. Gheorghiu-Dej’s successful efforts to expand Romania’s foreign relations, especially those with the West, were evident at his March 1965 funeral, at which 33 foreign delegations were present, including a special French envoy sent from General Charles de Gaulle. Gheorghiu-Dej’s policies of Romanian sovereignty and Western economic interaction set the stage for his successor, Nicolae Ceauşescu, to carry Romania’s new course even further.

Gheorghiu-Dej died of lung cancer in Bucharest on March 19, 1965. Some claim that he was intentionally irradiated during a visit to Moscow, due to his political stance. Gheorghe Apostol argued that he had been appointed successor by Gheorghe Gheorghiu-Dej himself, and was in any case perceived as such in 1965. Ion Gheorghe Maurer, who had developed a hostility towards Apostol, made sure that he was prevented from gaining power, rallying the Party leadership around Nicolae Ceauşescu - a protégé of Gheorghiu-Dej, and a figure of secondary importance at the time. The highest-ranking Soviet Bloc intelligence defector, Lt. Gen. Ion Mihai Pacepa described a conversation with Nicolae Ceauşescu, who told him about "ten international leaders the Kremlin killed or tried to kill"; Gheorghiu-Dej was one of them.

Gheorghiu-Dej was buried in a mausoleum in Liberty Park in Bucharest. In 1990, after the Romanian Revolution, his body was exhumed and reburied in a city cemetery. The Polytechnic Institute of Bucharest, renamed to Polytechnic Institute "Gheorghe Gheorghiu-Dej" Bucharest in his honor, is now known as the Polytechnic University of Bucharest. Also, the city of Oneşti was named Gheorghe-Gheorghiu Dej.

Gheorghiu-Dej was married to Maria Alexe and they had two daughters: Vasilica (1928–1987) and Constantina (b. 1931).