The Amazon basin is characterized by a strong interplay between the atmosphere and vegetation. Anthropogenic land use and land cover change (LULCC) affects vegetation and the exchange of energy and water with the atmosphere. Here we have assessed potential LULCC impacts on climate and natural vegetation dynamics over South America with a regional Earth system model that also accounts for vegetation dynamics. The biophysical and biogeochemical impacts from LULCC were addressed with two simulations over the CORDEX-South America domain. The results show that LULCC imposes local and remote influences on South American climate. These include significant local warming over the LULCC-affected area, changes in circulation patterns over the Amazon basin during the dry season, and an intensified hydrological cycle over much of the LULCC-affected area during the wet season. These changes affect the natural vegetation productivity which shows contrasting and significant changes between northwestern (around 10% increase) and southeastern (up to 10% decrease) parts of the Amazon basin caused by mesoscale circulation changes during the dry season, and increased productivity in parts of the LULCC-affected areas. We conclude that ongoing deforestation around the fringes of the Amazon could impact pristine forest by changing mesoscale circulation patterns, amplifying the degradation of natural vegetation caused by direct, local impacts of land use activities.