Dom Mintoff was born in Bormla, Malta. He commenced schooling at a public school, attended for some time the Bishop's seminary and later, graduated from the University of Malta, first, with a Bachelor of Science (1937) and later as an architect and civil engineer (1939). In that same year he was given a scholarship from the Sir Cecil Rhodes foundation, and he continued his studies at Hertford College, Oxford University, which led him to receive Masters in Science and Engineering in 1943. He met his future wife, Moira de Vere Bentinck, during his studies in England, and together they had two daughters, Anne and Yana. He continued to practice his profession in England until 1943, when he returned to Malta.

Mintoff entered the political scene in 1935 as an assistant secretary in a Bormla Labour Party club. He was appointed General Secretary of the Labour Party in 1935 but in 1937 had to resign to continue studying abroad. On his return from England he was first reappointed General Secretary.

Mintoff first held public office in 1945 when he was elected to the Government Council in the interests of the Labour Party. His tenure was to be short-lived: the Labour representatives resigned in protest at the plans for a massive post-War run-down at the Imperial dockyard. At the same time Mintoff was elected Deputy Leader of the Party with such a wide margin that placed him in an indisputable position as the successor, if not a challenger, to the Leader Paul Boffa.

Autonomous government was restored to Malta in 1947 and in the elections that year the Labour Party won an absolute majority in the face of a fragmented opposition. Mintoff was appointed Deputy Prime Minister and Minister of Public Works and Reconstruction presiding over large post-War public projects. However, Mintoff's strong position and ambition led to a series of Cabinet crises. A split in the Labour Party came about when Boffa, who was ready for compromise and moderation with the colonial authorities, resigned and formed the Malta Workers Party and Mintoff refounded the Labour Party as the "Malta Labour Party" of which he assumed leadership. The split resulted in the weakening of both parties and it was not until 1955 after remaining out of government for three consecutive legislatures, that the Labour Party was elected in office with Mintoff as Prime Minister.

This government's main political platform -- integration with the UK -- led to a deterioration of the Party's relations with the Catholic Church, leading to interdiction by the Church. The Labour Party lost the subsequent two elections in 1962 and 1966 and boycotted the Independence celebrations in 1964. The Party was returned to power in 1971 and reelected in 1976 with a clear majority. Apart from the premiership, between 1971 and 1981 Mintoff also held responsibility for foreign and Commonwealth affairs. In this role between 1971 and 1972 he personally led negotiations with the British government over the closure of the military base which took place in 1979, an event considered by most as the climax of his political career. During Mintoff's tenure of office in the 1970s Malta saw an economic boom which (unlike previous booms) resulted in a general increase in the standard of living, in particular of the working class. This was mostly due to government's policy which aimed at maximising exports. It was also due to new social programmes as well as government's pro-active policies.

For the 1981 elections, the oppostion Partit Nazzjonalista, reinvigorated with a new leader, looked set for a serious challenge to Mintoff. In fact, in that election, the Partit Nazzjonalista managed an absolute majority of votes but gerrymandered districts meant that it only managed 31 seats to the Labour Party's 34. Mintoff said that he would not be ready to govern in such conditions and hinted that he would call for fresh elections within six months. However, this was not to be: Mintoff eventually accepted the President's invitation to form a government. This led to a political crisis whose effects continued through much of the 1980s, as well as increasing political violence in the street such as the Black Monday incident. Mintoff was meanwhile laying the foundations for a succession: in 1982, Karmenu Mifsud Bonnici, Deputy Party Leader since 1980, was appointed Designated Leader, co-opted in Parliament and given a Ministerial portfolio. Mifsud Bonnici stepped in as Prime Minister and Leader of the Labour Party in 1984 when Mintoff resigned both posts. Mintoff, however, retained his parliamentary seat, a fact which, many claimed, gave him much behind-the-scenes leverage.

Labour initiatied discussions with the Opposition, so that Constitutional amendments allowing for bonus seats for the Party which obtained an absolute majority of first-preference votes but not a parliamentary majority where doney. It is claimed that Mintoff was instrumental in convincing his former colleagues to approve these amendments. A repeat of 1981 was thus avoided and the Partit Nazzjonalista went on to win the 1987 elections. The Labour Party went into opposition for the first time in sixteen years.

Mintoff generally held a low profile during this tenure of the Nationalist government (1987–1996) with the exception of an episode in 1989 when the Government decided to build a power station in Delimara close to his villa. Mintoff was also rumoured to have taken de facto leadership of the Party following the electoral defeats of 1987 and 1992. Labour return to power in 1996 under the leadership of Alfred Sant did not change things much and Mintoff seemed happy with the quiet life of a backbencher. However, there was a growing rift between Mintoff, seen as Old Labour, and Alfred Sant who was intent on detaching the Party from the image it had assumed in the 1980s. Things came to a head in 1998 when the Labour government was negotiating the lease of sealine to be developed in a yacht marina in the Three-Cities. This concession in Mintoff's former political stronghold, would have meant that access to the area would have to be restricted. Mintoff's made a strong reaction, some claiming that it was the result of pent-up frustration at being sidelined for many years and Sant's reply was even angrier: at a press conference in the locality Sant went as far as calling Mintoff a "traitor". In response, Mintoff hinted that not only would he abstain on the parliamentary vote on the lease, he would vote against; Sant, raising the stakes, replied that if the government were defeated as a result (it would as it had only a one-seat majority) it would be interpreted as a vote of no-confidence and he would resign and call on the President to dissolve Parliament. This was the way things turned out to be. Mintoff, undeterred, voted against, Sant resigned and Parliament was dissolved. In elections that year, the first since the War when Mintoff was not on the ballot paper, the Malta Labour Party, divided and deep in mid-term blues, lost heavily.

Mintoff has not stood in any election as a candidate since. He was, however, involved in 2003 in the unsuccessful campaign to keep Malta out of the EU.

Known as Il-Perit (The Architect), Tal-Pipa (The pipe smoker) Tal-Bokkla (The man with the buckle) or "Il-Bozza Hamra" (The red light), he had an avid interest in horses and had the habit of wearing a massive buckle with a horse insignia during mass meetings. Other than horse-riding and reading, he has a passion for the traditional bowls game il-boċċi, that he played in his country house at Delimara. He was known to go to his daily swim at It-Tawwalija creek in Delimara all year round. His favourite expletive reserved to his opponents is ġidra (turnip), which in Maltese denotes stupidity and ignorance. People still recall that during the 1960s politico-religious war, his followers replaced effigies of saints with his own portraits, to which they adorned with flowers and lit candles, in a spiteful reaction towards the opposing church.