Linguistic evidence suggests that the Amuesha migrated to the eastern foothills of the Andes at least 2,000 years ago. For centuries prior to the arrival of the Spaniards the Amuesha were in constant contact with other jungle groups who came to the Cerro de Sal (Salt Mountain) in Amuesha territory to obtain salt for their own use and for barter with more distant groups. Linguistic, archaeological, and mythological evidence suggest that the Amuesha were later dominated by the Incas and were forced to work for them. The first important contact with the Spaniards was in 1635, when the Franciscans established a mission among the Amuesha and neighboring Campa groups (Asháninca, Ashéninca, and Nomatsiguenga) at Cerro de Sal. When hostilities broke out a few years later, the mission was destroyed. It was reestablished in 1671, and by 1673 the indigenous population reached more than 1,000. Again hostilities destroyed the efforts of the Franciscans until 1709. In 1742 the Campa groups and the Amuesha, led by Juan Santos Atahualpa Inca, rebelled and drove all outsiders from the area. More than 100 years passed before mission efforts were renewed in 1881 at Oxapampa on the headwaters of the Pozuzo.
In the 1860s colonists from the Tyrolean Alps established themselves along the Pozuzo and spread to the Palcazu; in 1890 the Peruvian Corporation was ceded 500,000 hectares along the Perene and Ene rivers. Thus, outsiders gradually dispossessed the Amuesha of the territory along their western and southern boundaries. In the southeast, the Ashéninca Campa now claim former Amuesha territory. The Amuesha have been in continuous contact with the outside world for more than 100 years, but today the contact is even more intense following the influx of colonists from the highlands after the construction of the Marginal Highway, which transverses the whole of Amuesha territory.