A woman nicknamed Johnsy (her full name is Joanna) has come down with pneumonia, and is now close to death. Outside the window of her room, the leaves fall from a vine. Johnsy decides that when the last leaf drops, she too will die, while her best friend Sue, who stays with her, tries to tell her to stop thinking so pessimistically.

In the same apartment building, an elderly, frustrated artist named Behrman lives below Johnsy and Sue. Behrman has been claiming that he will paint a masterpiece, even though he has never even attempted to start. Sue visits Behrman, telling him that Johnsy, who is dying of pneumonia, has come to believe that she will die when the last leaf falls off of the vine outside her window. Behrman scoffs at this as foolishness, but—as he is protective of the two young artists—he decides to visit Johnsy and see the vine from her window.

In the night, a storm comes with wind howling and rain splattering against the window. Sue closes the curtains and tells Johnsy to go to sleep, even though there is still one leaf left on the vine. Johnsy protests against having the curtains closed, but Sue insists because she does not want Johnsy to see the last leaf fall. In the morning, Johnsy wants to see the vine to be sure that all the leaves are gone, but to their surprise, there is still one leaf left.

The leaf does not fall that day, nor does it fall overnight, nor the next day. Johnsy believes that the leaf stayed there to show how wicked she was, and that she sinned in wanting to die. She begins to live.

When Johnsy is strong enough, Sue reveals to her that their neighbor Behrman has died of pneumonia, and that the one remaining leaf is in fact his masterpiece done for Johnsy's sake to live.