The origins of the narrator and the hero in the fictitious small town of Kaisersaschern on the Saale, the name of Zeitblom's apothecary father, Wohlgemut, and the description of Adrian Leverkühn as an old-fashioned German type, with a cast of features "from a time before the Thirty Years War", evoke the old post-medieval Germany. In their respective Catholic and Lutheran origins, and theological studies, they are heirs to the German Renaissance and the world of Dürer and Bach, but sympathetic to, and admired by, the "keen-scented receptivity of Jewish circles."
They are awakened to musical knowledge by Wendell Kretzschmar, a German American lecturer and musicologist who visits Kaisersaschern. After schooling together, both boys study at Halle – Adrian studies theology; Zeitblom does not, but participates in discussions with the theological students – but Adrian becomes absorbed in musical harmony, counterpoint and polyphony as a key to metaphysics and mystic numbers, and follows Kretzschmar to Leipzig to study with him.
Zeitblom describes "with a religious shudder" Adrian's embrace with the woman who gave him syphilis (whom Adrian names "Esmeralda" after the butterfly that fascinates his father), how he worked her name in note-ciphers into his compositions, and how the medics who sought to heal him were all prevented from effecting a cure by mysterious and deadly interventions. Zeitblom begins to perceive the demonic, as Adrian develops other friendships, first with the translator Rüdiger Schildknapp, and then after his move to Munich with the handsome young violinist Rudi Schwerdtfeger, Frau Rodde and her doomed daughters Clarissa and Ines, a numismatist named Dr. Kranich, and two artists named Leo Zink and Baptist Spengler.
Zeitblom insists, however, on the unique closeness of his own relationship to Adrian, for he remains the only person whom the composer addresses by the familiar pronoun. Adrian meets the Schweigestill family at Pfeiffering, in the country an hour from Munich, which later becomes his permanent home and retreat.
He lives at Palestrina in Italy with Schildknapp in 1912, and Zeitblom visits them. It is there that Adrian, working on music for an operatic adaptation of Shakespeare's Love's Labour's Lost, has his long dialogue with a Mephistopheles figure who appears either objectively or out of his own afflicted soul. In these central pages, the fulcrum of the story, Zeitblom presents Adrian's manuscript of the conversation. The demon, speaking in archaic German, claims Esmeralda as the instrument by which he entraps Adrian and offers him twenty-four years' life as a genius – the supposed incubation period of his syphilis – if he will now renounce the warmth of love. The dialogue reveals the anatomy of Leverkühn's thought.
Adrian then moves permanently to Pfeiffering, and in conversations with Zeitblom confesses a darker view of life. Figures of a demonic type appear, such as Dr. Chaim Breisacher, to cast down the idols of the older generation.
In 1915, Ines Rodde marries, but forms an adulterous love for Rudi Schwerdtfeger. Adrian begins to experience illnesses of retching, headaches and migraines, but is producing new and finer music, preparing the way for his great work, the oratorio Apocalypsis cum Figuris ('The Apocalypse with Figures'). Schwerdtfeger woos himself into Adrian's solitude, asking for a violin concerto that would be like the offspring of their platonic union.
By August 1919 Adrian has completed the sketch of Apocalypsis. There is also a new circle of intellectual friends, including Sextus Kridwiss, the art-expert; Chaim Breisacher; Dr. Egon Unruhe, the palaeozoologist; Georg Vogler, a literary historian; Dr. Holzschuher, a Dürer scholar; and the saturnine poet Daniel zur Höhe. In their discussions they declare the need for the renunciation of bourgeois softness and a preparation for an age of pre-medieval harshness. Adrian writes to Zeitblom that collectivism is the true antithesis of Bourgeois culture; Zeitblom observes that aestheticism is the herald of barbarism.
Apocalypsis is performed in Frankfurt in 1926 under Otto Klemperer with 'Erbe' as the St. John narrator. Zeitblom describes the work as filled with longing without hope, with hellish laughter transposed and transfigured even into the searing tones of spheres and angels.
Adrian, producing the concerto which Rudi solicited, attempts to evade his contract and obtain a wife by employing Rudi as the messenger of his love. She however prefers Rudi himself, and not Adrian. Soon afterwards Rudi is shot dead in a tram by Ines out of jealousy. As Adrian begins to plan the second oratorio The Lamentation of Doctor Faustus, in 1928, his sister's child Nepomuk is sent to live with him. The boy, who calls himself "Echo", is beloved by all.
As the work of gigantic dimensions develops in Adrian's mind, the child falls ill and dies, and Adrian, despairing, believes that by gazing at him with love, in violation of his contract, he has killed him with poisonous and hellish influences.
The score of the Lamentation is completed in 1930, Adrian summons his friends and guests, and instead of playing the music he relates the story of his infernal contract, and descends into the brain disease which lasts until his death ten years later.
Zeitblom visits him occasionally, and survives to witness the collapse of Germany's "dissolute triumphs" as he tells the story of his friend.