Darién (World Heritage site) was first reached by Europeans in 1501 and was seen by Christopher Columbus (Columbus, Christopher) on his last voyage. The first successful European settlement on the mainland of the Americas, Santa María de la Antigua del Darién, was begun in 1510 on the western side of the Gulf of Urabá. From this colony Vasco Núñez de Balboa (Balboa, Vasco Núñez de) made his famous march to the Pacific Ocean in 1513. A few years later some colonists left the Darién settlement to found Panama City; eventually, Santa María was abandoned. Another short-lived attempt at colonization was made in the 17th century, when a Scottish trading company founded a settlement about halfway between Portobelo, Panama, and Cartagena, Colombia.

The towns of Darién remain isolated in spite of the construction of small airfields across the region. Towns close to the international border include Jaqué, Yaviza, and El Real de Santa María (in Panama) and Juradó, Salaquí, and Ríosucio (in Colombia). Notable indigenous groups are the Chocó (specifically the Embera and Wounaan, or Waunana) and the Kuna (Cuna); estimates for their combined local populations range widely, from 1,200 to some 25,000. They have traditionally lived in villages scattered throughout the forest, but some families have relocated to towns and cities. In Darién plantains, corn (maize), and rice are cultivated, livestock is raised, and lumber is cut and milled. The Pan-American Highway does not traverse Darién, which effectively blocks land transportation between Central and South America.

A pair of contiguous parks administer a large part of the region—Darién National Park in Panama and Los Katíos National Park in Colombia. The Panamanian park was established as the Alto Darién Forest Reserve in 1972 and elevated to national park status in 1980; it covers some 2,305 square miles (5,970 square km). The Colombian park was established in 1974 and extended in 1980 to cover some 280 square miles (720 square km). UNESCO added Darién National Park to the World Heritage List (World Heritage site) in 1981, followed by Los Katíos in 1994. Both areas protect a highly diverse assortment of flora and fauna. Among the wildlife are capybaras (capybara), jaguars, ocelots (ocelot), giant anteaters, howler monkeys, harpy eagles, caimans, American crocodiles, and the endemic grey-headed chachalaca (Ortalis cinereiceps). Annual rainfall in Darién varies from a minimum of 70 inches (1,800 mm) to a maximum of 180 inches (4,500 mm).

Since the late 1990s, Darién has been the site of increased conflict as Colombian groups (guerrillas, narcotics traffickers, and right-wing paramilitary forces) cross the border into Panama and smugglers bring over a growing number of refugees from Colombia's civil war. The Panamanian government's inability to defend the region has become a source of growing concern and political debate within Panama.