Across South America, the expansion of commodity land uses has underpinned substantial economic development at the expense of natural land cover and associated ecosystem services. Here, we show that such human impact on the continent’s land surface, specifically land use conversion and natural land cover modification, expanded by 268 million hectares (Mha), or 60%, from 1985 to 2018. By 2018, 713 Mha, or 40%, of the South American landmass was impacted by human activity. Since 1985, the area of natural tree cover decreased by 16%, and pasture, cropland, and plantation land uses increased by 23, 160, and 288%, respectively. A substantial area of disturbed natural land cover, totaling 55 Mha, had no discernable land use, representing land that is degraded in terms of ecosystem function but not economically productive. These results illustrate the extent of ongoing human appropriation of natural ecosystems in South America, which intensifies threats to ecosystem-scale functions.