Tropical forests are global climate regulators through their interaction with hydrological and biogeochemical cycles. Despite extensive research on deforestation in South America and its global impact, the role of the largely intact Guiana Shield forests, north of the Amazon, has not yet been considered as part of this climate system. We use a regional climate model with a realistic deforestation scenario to test the impact of deforestation in the Guiana Shield on climate throughout South America. We show that replacing ~28% of the current Guiana Shield rainforest with savannah leads to multi-scale impacts across South America, through vegetation-land-atmosphere interactions that disrupt the initial phase of two major 'atmospheric rivers': the Caribbean low-level Jet and the South American low-level jet (SALLJ). Our climate simulations suggest that following deforestation, locally, precipitation and runoff would more than double in lowland forests, whilst mean annual temperatures would increase by up to 2.2 °C in savannahs. Regionally, significant wetting is simulated in northern South America (April−September) and the western Amazon (October–March), while temperatures increase up to 2 °C in central and eastern Amazon, causing more dry months in up to 64% of the Amazon basin. Reduction of moisture transfer by the SALLJ of 2.2% of total annual flow causes noticeable and highly diverse spatial changes in simulated monthly rainfall in la plata basin (LPB). These results highlight the potential consequences of land cover change in a sensitive hot-spot with hydro-climatic impacts 1000 km west and 4000 km south. Such multi-scale perturbations can severely impact biodiversity and ecosystem services across South America, including agriculture in LPB. Recognition of the far field effects of localised deforestation in key areas is urgently needed to improve development plans for a sustainable future.