There is no official best book by Thomas Mann, and the choice of main work depends on the criterion. The most cited titles are Buddenbrooks (1901), Death in Venice (1912), The Magic Mountain (1924), the tetralogy Joseph and His Brothers (1933 to 1943), and Doctor Faustus (1947).
If the criterion is official recognition and popularity, the name is Buddenbrooks, his first novel. The Swedish Academy cited it as the main reason for the 1929 Nobel, and Wikipedia describes it as Mann's most popular novel, above all in Germany. It follows the Buddenbrook family, grain merchants of Lübeck, from 1835 to 1877, and draws on the author's own family.
If the criterion is the ambition of the ideas, the strong candidate is The Magic Mountain. Hans Castorp, a young engineer from Hamburg, goes to visit a cousin in a sanatorium for tuberculosis patients in the Swiss Alps, plans to stay a short time, and stays seven years. During his stay he meets Settembrini, Naphta, and Madame Chauchat, who place him before politics, philosophy, love, illness, and death. The book was born from a visit of a few weeks that Mann made in 1912 to his wife, who had been admitted to a sanatorium in Davos, and it is read both as a novel of formation and as a satire of that genre. As for Doctor Faustus, with the fictional composer Adrian Leverkühn, it deals, through the life of the composer, with the crisis of Germany in the first half of the twentieth century, in a narrative written between 1943 and 1946.
For someone who has never read Mann, there are three ways in: Buddenbrooks, a family saga in chronological order; Death in Venice, much shorter; or The Magic Mountain, the longest and the one that asks the most patience. This is a suggestion for reading, not a ranking: criticism does not elect a single best book.
On Clavis: The Magic Mountain.