Located on the eastern fringe of the ancient Maya heartland, Northern Belize supported many settlements through history without producing any cities of the size or grandeur of Caracol, which lies further south in Belize, or Tikal in Guatemala. It was home to important river trade routes that linked the interior with the coast: the north's major Maya site, Lamanai, commanded one of these routes and grew to a city of up to 35,000 people during the Maya peak, known as the Classic Period. The city at Lamanai continued to serve as a Maya center until the Spanish arrived in the 16th century.

Meanwhile, another city grew up further west at La Milpa. During the late Classic Period, La Milpa was home to 46,000 people, but archaeologists believe the city came to an abrupt end in the 9th century AD, possibly due to environmental and economic stresses brought on by drought.

A Spanish expedition into Northern Belize from the Yucatán in 1544 led to the conquering of many of the region's Maya settlements and, later, the creation of a series of Spanish missions distantly controlled by a priest at Bacalar in the southeastern Yucatán. Maya rebellion was fierce, and after a series of battles the Spanish were driven out of the area for good in 1640.

British loggers began moving into the region in search of mahogany in the 18th century. They encountered sporadic resistance from the now weakened and depleted Maya population, which had been ravaged by European-introduced diseases.

In 1847 the Maya in the Yucatán rose up against their Spanish-descended overlords in the War of the Castes ('Guerra de Castas' in Spanish), a vicious conflict that continued in diminishing form into the 20th century. Refugees from both sides of the conflict took shelter in northern British Honduras (as Belize was then called), with people of Spanish descent founding the towns of Orange Walk and Corozal, and the Maya moving into the forests and countryside. It wasn't surprising that intermittent hostilities took place in British Honduras. One group of Maya, the Icaiché, was repulsed from Orange Walk after fierce fighting in 1872. The border between Mexico and British Honduras was not agreed upon between the two states until 1893.

Caste War migrants from the Yucatán laid the foundations of modern Northern Belize by starting the area's first sugarcane plantations. Despite the sugar industry's many vicissitudes, it is now the backbone of the Northern Belize economy, with some 900 cane farms in the region.