The South American Monsoon System is responsible for the majority of precipitation in the continent, especially over the Amazon and the tropical savannah, known as 'Cerrado'. Compared to the extensively studied subtropical and temperate regions the effect of the Medieval Climate Anomaly (MCA) on the precipitation over the tropics is still poorly understood. Here, we present a multiproxy paleoprecipitation reconstruction showing a consistent change in the hydrologic regime during the MCA in the eastern Amazon and 'Cerrado', characterized by a substantial transition from humid to drier conditions during the Early (925-1150 C.E.) to Late-MCA (1150-1350 C.E.). We compare the timing of major changes in the monsoon precipitation with the expansion and abandonment of settlements reported in the archeological record. Our results show that important cultural successions in the pre-Columbian Central Amazon, the transition from Paredão to Guarita phase, are in agreement with major changes in the hydrologic regime. Phases of expansion and, subsequent abandonment, of large settlements from Paredão during the Early to Late-MCA are coherent with a reduction in water supply. In this context we argue that the sustained drier conditions during the latter period may have triggered territorial disputes with Guarita leading to the Paredão demise.