Mann was born Paul Thomas Mann in Lübeck, Germany and was the second son of Thomas Johann Heinrich Mann (a senator and a grain merchant), and his wife Júlia da Silva Bruhns (a Brazilian with partially German ancestry who emigrated to Germany when seven years old). His mother was Roman Catholic, but Mann was baptised into his father's Lutheran faith. Mann's father died in 1891, and his trading firm was liquidated. The family subsequently moved to Munich. Mann attended the science division of a Lübeck gymnasium, then spent time at the Ludwig Maximillians University of Munich and Technical University of Munich where, in preparation for a journalism career, he studied history, economics, art history, and literature. He lived in Munich from 1891 until 1933, with the exception of a year in Palestrina, Italy, with his novelist elder brother Heinrich. Thomas worked with the South German Fire Insurance Company 1894–95. His career as a writer began when he wrote for Simplicissimus. Mann's first short story, "Little Herr Friedemann" (Der Kleine Herr Friedemann), was published in 1898.

In 1905, he married Katia Pringsheim, daughter of a prominent, secular Jewish family of intellectuals. They had six children:

In 1929, Mann had a cottage built in the fishing village of Nidden (Nida, Lithuania) on the Curonian Spit, where there was a German art colony, and where he spent the summers of 1930-32 working on Joseph and his Brothers. The cottage now is a cultural center dedicated to him, with a small memorial exhibition. In 1933, after Hitler assumed power, Mann emigrated to Küsnacht, near Zürich, Switzerland, but received Czechoslovak citizenship and a passport in 1936. He then emigrated to the United States in 1939, where he taught at Princeton University. In 1942, the Mann family moved to Pacific Palisades, in west Los Angeles California, where they lived until after the end of World War II. On 23 June 1944 Thomas Mann was naturalized as a citizen of the United States. In 1952, he returned to Europe, to live in Kilchberg, near Zürich, Switzerland.

He never again lived in Germany, though he regularly traveled there. His most important German visit was in 1949, at the 200th birthday of Johann Wolfgang von Goethe, attending celebrations in Frankfurt am Main and Weimar, as a statement that German culture extends beyond the new political borders.

In 1955, he died of atherosclerosis in a hospital in Zürich and was buried in Kilchberg. Many institutions are named in his honour, most famously the Thomas Mann Gymnasium of Budapest.

Thomas Mann's works were first translated into English by H. T. Lowe-Porter. Her translations have become classics in their own right and have contributed enormously to Mann's popularity in the English-speaking world.

During World War I Mann supported Kaiser Wilhelm II's conservatism and attacked liberalism. Yet in Von Deutscher Republik (1923), as a semi-official spokesman for parliamentary democracy, Mann called upon German intellectuals to support the new Weimar Republic. He also gave a lecture at the Beethovensaal in Berlin on 13 October 1922, which appeared in Die neue Rundschau in November 1922, in which he developed his eccentric defence of the Republic, based on extensive close readings of Novalis and Walt Whitman. Hereafter his political views gradually shifted toward liberal left and democratic principles.

In 1930 Mann gave a public address in Berlin titled "An Appeal to Reason", in which he strongly denounced National Socialism and encouraged resistance by the working class. This was followed by numerous essays and lectures in which he attacked the Nazis. At the same time, he expressed increasing sympathy for socialist ideas. In 1933 when the Nazis came to power, Mann and his wife were on holiday in Switzerland. Due to his very vociferous denunciations of Nazi policies, his son Klaus advised him not to return. But Thomas Mann's books, in contrast to those of his brother Heinrich and his son Klaus, were not among those burnt publicly by Hitler's regime in May 1933, possibly since he had been the Nobel laureate in literature for 1929 (see below). Finally in 1936 the Nazi government officially revoked his German citizenship. A few months later he moved to California.

However, already in 1933, in a personal letter dated 26 October 1933 but published only recently (in the feuilleton section of the Frankfurter Allgemeine Zeitung dated Oct. 30, 2007), Thomas Mann expressed views on Nazism, which corresponded to the much later novel Doktor Faustus. In the novel, the author refers in several places to the historical debt of the German population, leading to World War II with all its cruelty.

During the war, Mann made a series of anti-Nazi radio-speeches, Deutsche Hörer! ("German listeners!"). They were taped in the USA and then sent to Great Britain, where the BBC transmitted them, hoping to reach German listeners.