Arguably Hopper’s best known painting, Nighthawks depicts four people in a diner at night. Despite their close proximity, there is no indication of interaction between the figures. The contrast between a brightly lit interior and a darkened city street adds to the sense of isolation that pervades the painting. About the work, Hopper stated, "I didn’t see it as particularly lonely. I simplified the scene a great deal and made the restaurant bigger. Unconsciously, probably, I was painting the loneliness of a big city."

Nighthawks began as a series of sketches, with the details of the restaurant based on Hopper’s visits to diners and coffee shops to study items such as coffee urns and architecture. In addition to Hopper’s years in New York City, a number of other influences are also apparent in the painting. Gail Levin notes that Hopper drew on many different sources for Nighthawks, including cinema, literature, and the work of other artists: "Together, the composition, content, and lighting betray Hopper’s fascination with cinema[,] . . . Vincent Van Gogh’s sinister Night Café . . . and Ernest Hemingway’s ‘The Killers.’"

Hopper finished the painting over the span of a month-and-a-half of work in New York City, and the naming of the work was left to his wife, Jo, who thought that the words "Night Hawks" appropriately captured the mood of the scene. After acquiring the painting in 1942, the Art Institute of Chicago further honored Hopper and Nighthawks by awarding him the Ada S. Garrett Prize.