The novel is a re-shaping of the Faust legend set in the context of the first half of the 20th century and the turmoil of Germany in that period. The story centers on the life and work of the (fictitious) composer Adrian Leverkühn. The narrator is Leverkühn's childhood friend Serenus Zeitblom, who writes in Germany between 1943 and 1946.
Leverkühn's extraordinary intellect and creativity as a young man mark him as destined for success, but his ambition is for true greatness. He strikes a Faustian bargain for creative genius: he intentionally contracts syphilis, which deepens his artistic inspiration through madness. He is subsequently visited by a Mephistophelean being (who says, in effect, "that you can only see me because you are mad, does not mean that I do not really exist"), and, renouncing love, bargains his soul in exchange for twenty-four years of genius. His madness – his daemonic inspiration – leads to extraordinary musical creativity (which parallels the actual innovations of Arnold Schoenberg).
Leverkühn's last creative years are increasingly haunted by his obsession with the Apocalypse and the Last Judgment. He feels the inexorable progress of his neuro-syphilitic madness leading towards complete breakdown. As in certain of the Faust legends, he calls together his closest friends to witness his final collapse. At a chamber-reading of his cantata "The Lamentation of Doctor Faust", he ravingly confesses his demonic pact before becoming incoherent. His madness reduces him to an infantile state in which he lives under the care of his relatives for another ten years.
Leverkühn's life unfolds in the context of, and in parallel with, the German cultural and political environment which led to the rise and downfall of Nazi Germany. But the predisposing conditions for Leverkühn's pact with the devil are set in character, and in the artistic life, the artistic processes themselves, not merely as political allegory. The interplay of layers between the narrator's historical situation, the progress of Leverkühn's madness, and the medieval legends with which Leverkühn consciously connects himself makes for an overwhelmingly rich symbolic network, an ambiguous complexity that cannot be reduced to a single interpretation.