The Florentine poet and scholar Poliziano, or Angelo Ambrogini, uses the classical tale of Orpheus and Eurydice in his fifteenth-century drama, which includes musical numbers highlighting key points in the plot. Orfeo was composed for Cardinal Gonzaga of Mantua. Poliziano also employs an unconventional structure that includes a framing device. The ending of his version also includes a violent ending to the story: Orpheus suffers fierce retaliation for his renunciation of love.

The drama begins with a sylvan scene that frames the main story within an encounter among several shepherds: Mopsus, Aristaeus, and Thyrsis. (This scene is drawn from Virgil's version.) While the shepherds are looking for an animal lost in the woods, Aristaeus is stricken with love for the nymph Eurydice, but it seems she already has a lover. The others urge caution, but he pursues her nonetheless. When he reaches her, she rebuffs his advances and flees. Sadly, she encounters a serpent (offstage) and dies from its fatal bite. As her sister nymphs begin their mourning song, the audience meets Orpheus, who enters with his lyre, singing of the hero Hercules.

When he learns of the tragedy, the inconsolable Orpheus fiercely laments his loss, calling out to nature's forces to hear him. Resolved to recover his beloved, Orpheus makes the bold decision to go to the underworld, Tartarus (or Hades), and bring her back. Well aware of the power of his music, he hopes that it will serve him well in charming the deities that govern the underworld; perhaps even Death itself will be moved to help reunite the lovers.

Orpheus sets off for Tartarus and, upon reaching the gates, plays and sings with heartfelt charm. He succeeds in having the gates opened to him. Progressing to the interior, he meets Pluto (Hades), ruler of the underworld, and Prosperpina (Persephone), his female consort. So powerful is Orfeo's music, Pluto tells him, that it has made everything stand still. Proserpina is deeply moved by the lovers' plight and by the music.

When Orpheus requests Eurydice's return, she recommends his plea be granted. Pluto agrees to let Eurydice go; Orpheus will go first and she will follow. There is one strict condition to which Orpheus must adhere, however: he must not look back to check that she is behind him. Orpheus is thrilled and proud that his music has proved so powerful, and he makes the necessary promise. Once he actually gets moving, however, he is plagued with doubt. Orpheus looks back. He watches helplessly as his darling is dragged back into the depths of Tartarus. Tisiphone, a Fury, prevents him from following her, and he must continue alone to the earth's surface.

Orpheus is devastated to suffer from this second loss and takes out his sorrow on love itself: as he bemoans this new turn of events, he also swears that he will never love again. A group of Maenads (or Bacchantes, cult followers of Bacchus, god of wine and revelry) is nearby, and they take issue with this declaration. Setting upon him in a frenzy, they literally tear Orpheus into pieces, leaving the forest drenched in his blood.