De Gasperi was born in Pieve Tesino in Trentino, at that time belonging to Austria-Hungary, now part of the Province of Trento in Italy. His father was a local police officer of limited financial means. From 1896 De Gasperi was active in the Social Christian movement. In 1900 he joined the Faculty of Literature and Philosophy in Vienna, where he played an important role in the inception of the Christian student movement. He was very much inspired by the Rerum Novarum encyclical issued by Pope Leo XIII in 1891. In 1904 he took an active part in the student demonstrations in favour of an Italian-language university. Imprisoned with other protesters during the inauguration of the Italian juridical faculty in Innsbruck, he was released after twenty days. In 1905, De Gasperi obtained a degree in philology.

In 1905 he began to work as editor of the newspaper La Voce Cattolica which was replaced in September 1906 by Il Trentino, and after a short time he became its editor. In his newspaper he often took positions in favour of a cultural autonomy for Welschtirol and in defence of Italian culture in Trentino, in contrast to the Germanisation plans of the German radical nationalists in Tyrol. However, he never questioned whether or not Trentino should belong to Austria–Hungary and claimed that, in the case of a referendum, 90% of the Trentino would nevertheless choose the popular Austrian emperor Franz Joseph I of Austria over the Italian motherland.

In 1911 he became a Member of Parliament for the Popular Political Union of Trentine (Italian: Unione Politica Popolare del Trentino - UPPT) in the Austrian Reichsrat, a post he held for 6 years. He was politically neutral during World War I, which he spent in Vienna. However, he sympathized with the ultimately unsuccessful efforts of pope Benedict XV (1914–1922) and Bl. Karl I of Austria to obtain an honourable peace and stop the war and mass warfare. When his home region was transferred to Italy in the post-war settlement, he accepted Italian citizenship.

In 1919 he was among the founders of the Italian People's Party (Italian: Partito Popolare Italiano - PPI), with Don Luigi Sturzo. He served as a deputy in the Italian Parliament from 1921 to 1924, a period marked by the rise of Fascism. He initially supported the participation of the PPI in Benito Mussolini’s first government in October 1922. As Mussolini's hold on the Italian government grew stronger, he soon diverged with the Fascists over constitutional changes to the powers of the executive and to the election system (the Acerbo Law), and to Fascist violence against the constitutional parties, culminating in the murder of Giacomo Matteotti. The PPI split, and De Gasperi became secretary of the remaining anti-Fascist group in May 1924. In November 1926, in a climate of overt violence and intimidation by the Fascists, the PPI was dissolved. De Gasperi was arrested in March 1927 and sentenced to four years in prison. The Vatican negotiated his release. A year and a half in prison nearly broke De Gasperi's health. After his release in July 1928, he was unemployed and in serious financial hardship, until in 1929 his ecclesiastical contacts secured him a job as a cataloguer in the Vatican Library, where he spent the next fourteen years until the collapse of Fascism in July 1943.

During World War II, he organized the establishment of the first (and at the time, illegal) Christian Democracy party, or Democrazia Cristiana, drawing upon the ideology of the Popular Party. In January 1943, he published "Ideas for reconstruction" (Italian: Idee ricostruttive) which amounted to a party programme for the party. He became the first general secretary of the new party in 1944. De Gasperi was the undisputed head of the Christian Democrats, the party that dominated Parliament for the next decades. Although his control of the DC appeared almost complete, he had to carefully balance different factions and interests, especially over relations with the Vatican, over social reform, and over foreign policy.

From 1945 to 1953 he was the prime minister of eight successive Christian Democratic governments. His eight-year rule remains a landmark of political longevity for one leader in modern Italian politics. During his successive governments Italy became a Republic (1946), signed a Peace Treaty with the Allies (1947), a member of the North Atlantic Treaty Organization (NATO) in 1949 and an ally of the United States, which helped to revive the Italian economy through the Marshall Plan. In the same years, Italy also became a member of theEuropean Coal and Steel Community (ECSC), which eventually transformed into the European Union (EU). After the liberation of Italy in June 1944, he had served as minister without portfolio and then as foreign minister. In December 1945, he became Prime Minister for the first time, leading a coalition government that included the Italian Communist Party (PCI) and Italian Socialist Party (PSI). Communist party leader Palmiro Togliatti acted as vice-premier. He tried to soften the terms of the pending Allied peace treaty with Italy and secured financial and economic aid through the European Recovery Program (Marshal Plan) – which was opposed by the Communists. In June 1946 a referendum was held to decide whether Italy would remain a monarchy or become a republic. The republican option won with 54%. As chief of the Italian delegation at the World War II peace conference in Paris, he obtained concessions from the Allies that guaranteed Italian sovereignty. Under the Paris Peace Treaties of 1947, the eastern border area was lost to Yugoslavia and the free territory of Trieste was divided between the two states. One of his most striking achievements in foreign policy was the Gruber-De Gasperi Agreement with Austria in September 1946 that established his home region, southern Tirol, as an autonomous region.

De Gasperi enjoyed considerable support in the US, where he was seen as the man who could oppose the rising tide of Communism – in particular the PCI, which was the biggest communist party in a Western European democracy. In January 1947 he visited the US. The chief goals of the trip were to soften the terms of the pending peace treaty with Italy, and to obtain immediate economic assistance. His ten-day tour, engineered by media mogul Henry Luce – the owner of Time Magazine – and his wife Clare Boothe Luce the future ambassador to Rome, was viewed as a media "triumph," prompting positive comments of a wide section of the American press. During his meetings in the US, he managed to secure a financially modest but politically significant US$100 million Eximbank loan to Italy. According to De Gasperi, public opinion would view the loan as a vote of confidence in the Italian Government and strengthen his position versus the Communist Party in the context of the emerging Cold War. The positive results strengthened De Gasperi’s reputation in Italy. He also came back with useful information on the incipient change in American foreign policy that would lead to the Cold War and in Italy the break with the Communists and left-wing Socialists and their removal from the government in May 1947.

The general elections in April 1948 were heavily influenced by the cold-war confrontation between the Soviet Union and the United States. After the Soviet-inspired February 1948 communist coup in Czechoslovakia, the US became alarmed about Soviet intentions and feared that, if the leftist coalition were to win the elections, the Soviet-funded Italian Communist Party (PCI) would draw Italy into the Soviet Union's sphere of influence. The election campaign remains unmatched in verbal aggression and fanaticism in Italy's history on both sides. The Catholic Church in Italy worked hard to encourage people to vote against communist candidates. In the US a campaign was launched to prevent a victory of the Communist dominated Popular Democratic Front (FDP - Italian: Fronte Democratico Popolare). Italian-Americans were encouraged to write letters to their relatives in Italy. The popular Italian-American singer Frank Sinatra made a Voice of America radio broadcast. The Central Intelligence Agency (CIA) funneled "black bag" contributions to anti-communist candidates with the approval of the National Security Agency (NSA) and President Truman. Joseph P. Kennedy and Claire Booth Luce helped to raise US$2 million for the Christian Democrat Party. Time Magazine backed the campaign and featured De Gasperi on its April 19, 1948 issue’s cover and in its lead story. (He would appear on a Time cover again on May 25, 1953, during the campaign for that year's election, with an extensive biography.) The Christian Democrats won a resounding victory with 48 percent of the vote (their best result ever, and not repeated since). The communists received only half the votes they had in 1946. The Christian Democrats won a parliamentary majority and De Gasperi formed a new centre-right government. In the following five years De Gasperi continued to run the country. In 1952, the party overwhelmingly endorsed his authority over the government and over the party. However, it was also the start of his decline. He came under increasing criticism from the emerging left wing in the party. Their main accusations were that he was too cautious in social and economic reform, that he stifled debate, and that he subordinated the party to the interests of government. When the Christian Democrats did not gain a majority in the elections of 1953, De Gasperi was unable to establish a workable government and was forced to resign as Prime Minister. The following year he also had to give up the leadership of the party.

Two months later, on August 19, 1954, he died in Sella di Valsugana, in his beloved Trentino. He is buried in the Basilica di San Lorenzo fuori le Mura, a basilica in Rome. The process for his beatification was opened in 1993.

He is considered to be one of the Founding fathers of the European Union. From the very beginning of European integration, De Gasperi, Robert Schuman and Konrad Adenauer met regularly. He helped organize the Council of Europe and supported the Schumann Plan, which in 1951 led to the foundation of the European Coal and Steel Community (ECSC) - a forerunner in the process of European integration. He was named president of the Community in 1954, and although the project eventually failed, De Gasperi helped develop the idea of the common European defence policy. In 1952 he received the Karlspreis (International Charlemagne Prize of the City of Aachen), an award by the German city of Aachen to people who contributed to the European idea and European peace.