During the colonization by the Spanish and first days of the first republic, the territory of Vaupes was part of the Province of Popayán, during the Greater Colombia. After the independence from Spain between 1821 and 1830 became part of the first version of the Boyacá Department. Between 1831 and 1857 the territory became part of the National Territory of Caquetá to later be part of the Sovereign State of Cauca. In 1886 became part of the then recently created Cauca Department.
With the expansion of the rubber industry and the industrial revolution, exploration for rubber reached the area briging colonizers that altered and in some cases extinguished the majority of the indigenous population.
The territory was first made into a territorial division in 1910 and functioned as Commissaries (Comisarias) with the town of Calamar as capital (located in present-day Guaviare) but later moved to the town of Mitú to make an "act of presence" near the border with Brasil. In 1963 Guainía segregated from the Vaupes and became a commissary. In 1977, Guaviare followed the same path.
The department's main economic activities feature logging and fishing, with much exportation to neighboring Brazil.
The vast majority of the population consists of indigenous inhabitants.
Because of its location in the Amazon jungle, it has no roads connecting it with the rest of the country or internally from settlement to settlement, and commerce and contact with the outside world is achieved through travel along the main rivers and by means of air travel. Several of the small settlements have airstrips with service to the department's capital, Mitú, and from there with the rest of the country.