Sue is a struggling artist who moved to New York from Maine to pursue her creative ambitions. She shares a third-floor apartment with Johnsy, whom she cares for deeply. When a winter epidemic strikes the city, Sue takes on a nurturing role, trying to maintain her sick friend's spirits while continuing her own commercial artwork to financially support them both. She is determined, practical, and highly protective of her roommate.

Johnsy is a young artist from California who moved to Greenwich Village to pursue her creative ambitions, holding onto a specific dream to one day paint the Bay of Naples. She falls severely ill during a winter epidemic, leaving her bedridden and fragile. Weakened and isolated by her sickness, she loses her motivation to fight the disease, instead fixing her attention on the falling leaves of an old vine outside her window.

Mike Behrman is an older, heavy-drinking painter in his sixties who lives on the first floor of Sue and Johnsy's building. A self-described failed artist, he has spent forty years attempting to create a masterpiece without success, earning a meager living by modeling for younger artists in the colony. Despite his gruff, blustering exterior and tendency to complain, he feels a fierce, protective duty toward the two young women living upstairs.

Mr. Pneumonia is the personified embodiment of the illness striking the Greenwich Village arts community. Characterized by the narrator as a predatory, icy-fingered older man rather than a chivalrous gentleman, this force of nature preys indiscriminately on the vulnerable residents of the area. He serves as the primary antagonistic force threatening Johnsy's survival and testing the bonds between the characters.

The Doctor is a busy medical professional attending to the victims of the winter epidemic sweeping through Greenwich Village. He is a practical, somewhat blunt man who assesses Johnsy's condition with clinical detachment. He firmly believes a patient's sheer will to live is more critical to their recovery than his medicines, prompting him to instruct Sue to find ways to motivate her sick friend.