Arrigo Boito, poet and writer, and founder of the artistic movement Scapigliatura, is known mostly for being a librettist more than a composer. Besides Mefistofele, his other opera as a musician is Nerone, which was represented after his death. As a librettist, the most important collaborations are with Giuseppe Verdi, with whom he worked during the second version of Simon Boccanegra and, most of all, Verdi's last two masterpieces Otello and Falstaff. With the nom de plume of Tobia Gorrio, he wrote what might be his most excessive and above the lines, as well as the funniest and most melodramatic, libretto: La Gioconda by Amilcare Ponchielli.
In the heavens, angels and cherubim sing the praises of God. The fallen angel Mefistofele challenges God affirming he can tempt the old Faust.
On Easter Sunday in Frankfurt, during the Sixteenth Century, groups of people gather to celebrate. The old Dr. Faust remarks to his student Wagner that spring brings hope and beauty. Faust notices a grey friar who has been following them. At night in Faust's study, the friar shows himself to be Mefistofele. Far from being terrified, Faust is intrigued and enters into a discussion with him culminating in an agreement by which he will give his soul to the devil on his death, in return for worldly bliss for what's left of his life.
In the garden near Margherita's house, Faust walks with the village girl while Mefistofele entertains and distracts her neighbour Marta. Faust asks her to be alone together and when she tells him that her mother shares her bed, Faust gives her some sleeping potion to make sure the old lady does not wake up. Mefistofele leads Faust toward the valley of Schirk, where the witches' sabbath is taking place. Faust sees a vision of Margherita in chains, with her throat cut.
Faust's vision was true: Margherita is in prison for poisoning her mother with the sleeping potion received by Faust and killing her own baby. Mefistofele helps Faust to enter the cell to rescue her, trying to convince her to flee. Margherita notices Mefistofele and starts thinking about her imminent execution. Dying, she prays for heaven to forgive her. Mefistofele pronounces her damned, but heavenly voices declare her saved.
Mefistofele has now transported Faust back in time to Ancient Greece. Helen of Troy and her followers are enjoying the exotic surroundings. Faust wins Helen's heart and in a passionate outpouring they declare their love to each other.
Faust, who's an old man again, is back in his study. He reflects on happy experiences but regrets that none of them ever struck him. Desperate for his final victory, Mefistofele urges him to embark on more exotic adventures but Faust, seizing his Bible, cries out for God’s forgiveness and Mefistofeles disappears to his own domain as heavenly forces claim the soul of the redeemed Faust.