Although the area was originally residential, markets have existed in the district since the 1840s. People moved into tenements in the Meatpacking District in the 1820s to escape epidemics in what was then the main part of New York. In 1884, New York named two acres of land after General Peter Gansevoort, a Revolutionary War hero and grandfather of Herman Melville. The neighborhood shifted to become a market, first for produce and after the development of reliable refrigeration, for meat. Gansevoort Market then became a commercial district.

In 1900, 250 slaughterhouses and packing plants filled the district; by the 1930s, those houses produced the nation's third-largest volume of dressed meats. The city, eager to retain the immediate supply of fresh meat and jobs, subsidized the industry throughout the early 20th century.

Few meatpacking companies still operate in the district. Boutiques and bars are more common than rump roasts these days, and the pressure to convert old market blocks into apartment buildings is severe. Located on the Hudson riverfront, the district's businesses face rising rents.