Act 1, Prologue
Orpheus Descending takes place in a dry-goods store in a small southern town. The play opens with Dolly and Beulah setting up a buffet supper. During their conversation, they reveal that Jabe Torrance has undergone surgery in Memphis and is now dying. Beulah reminisces about how Jabe essentially bought his wife, Lady, when she was just eighteen and heartbroken by David Cutrere. She also recounts that Lady's father, an Italian immigrant, acquired an orchard during Prohibition and turned it into a wine garden. Unfortunately, he made the mistake of selling liquor to a black man, which led the enraged locals to burn down his orchard, killing him in the process. Beulah speculates whether Lady knows that her despised husband led the mob. Additionally, Beulah mentions that Lady plans to reopen a "confectionery" (which will function as a sort of nightclub) in another part of the store.

Act 1, Scene 1
Carol Cutrere makes a phone call while the Temple sisters gossip about her. Val Xavier enters, followed shortly by Vee Talbott with one of her paintings. Val, the newcomer, quickly becomes the center of attention. Carol insists she has met him before in New Orleans, but Val denies it. Carol suggests they go out together, but Val, seeking employment, is not interested. Lady and Jabe then enter; Jabe appears ill and heads upstairs to bed, not before he and Lady express their mutual dislike. Carol continues to bother Val, revealing some of her past, including her days as a civil rights activist and an incident where she protested wearing only a potato sack, which led to her arrest for lewd vagrancy and a warning from a vigilante group to stay out of the county. Val picks up his guitar and leaves the store while the women continue their gossip.

Act 1, Scene 2
Two hours later, Val and Lady engage in conversation. Val complains about Carol's earlier attempt to seduce him and shows Lady his guitar, which bears autographs from famous blues musicians. Lady agrees to hire Val as a clerk, clarifying that she has no intention of becoming romantically involved with him.