Long before humans left their footprints in this region, a vast inland sea that had covered the landscape deposited its mark in a multitude of fossils. Eons later great indigenous nations flourished, the most important were the Muisca and the Guanes. During the Spanish occupation, gold mines flourished for a while near Bucaramanga. The region also had important ports of trade.

During Gran Granada’s struggle for independence from Spain, Eastern Colombia saw a lot of activity. Some of the sparks of this movement ignited in villages around San Gil. In 1819, independence forces, led by Simón Bolívar and Francisco de Paula Santander, won an important victory at Puente de Boyacá near Tunja. Villa del Rosario was the seat for the Congreso Constituyente in 1821 which formed Gran Colombia (Venezuela, Colombia and Ecuador). The first convention of this nascent nation was held in Villa de Leyva.

The end of the 19th century, Colombia experienced the 1,000-Day War. One of the main foci of fighting was Santander Department. The last —and bloodiest— battle of this civil war was fought at Palonegro, near Bucaramanga.

In the 1980s, both the FARC (Fuerzas Armadas Revolucionarias de Colombia) and ELN (Ejèrcito para la Liberación Nacional) began occupying great parts of Eastern Colombia, especially between the principal North-South highway and the Río Magdalena, the Sierra Nevada El Cocuy (including the national park) and the less-populated areas along the Venezuelan border, particularly in Norte de Santander Department. The mid-1990s brought paramilitary forces into the region; some villages, like Málaga and Capitanejo, suffered many killings during what the locals call “a reign of terror.” Many fled. Populations of principle towns, above all Bucaramanga and Cúcuta, swelled with these displaced people. During the third millennium and a new president, military forces commenced driving the guerrillas out of populated areas and soldiers continue to occupy villages. Remote zones still see armed confrontations between the government, guerrilla and paramilitary armies.