Soil organic carbon (SOC) plays an important role in climate change regulation notably through release of CO2 following land use change such a deforestation, but data on stock change levels are lacking. This study aims to empirically assess SOC stocks change between 1991 and 2011 at the landscape scale using easy-to-access spatially-explicit environmental factors. The study area was located in southeast Madagascar, in a region that exhibits very high rate of deforestation and which is characterized by both humid and dry climates. We estimated SOC stock on 0.1 ha plots for 95 different locations in a 43,000 ha reference area covering both dry and humid conditions and representing different land cover including natural forest, cropland, pasture and fallows. We used the Random Forest algorithm to find out the environmental factors explaining the spatial distribution of SOC. We then predicted SOC stocks for two soil layers at 30 cm and 100 cm over a wider area of 395,000 ha. By changing the soil and vegetation indices derived from remote sensing images we were able to produce SOC maps for 1991 and 2011. Those estimates and their related uncertainties where combined in a post-processing step to map estimates of significant SOC variations and we finally compared the SOC change map with published deforestation maps. Results show that the geologic variables, precipitation, temperature, and soil-vegetation status were strong predictors of SOC distribution at regional scale. We estimated an average net loss of 10.7% and 5.2% for the 30 cm and the 100 cm layers respectively for deforested areas in the humid area. Our results also suggest that these losses occur within the first five years following deforestation. No significant variations were observed for the dry region. This study provides new solutions and knowledge for a better integration of soil threats and opportunities in land management policies.