Global climate and land use changes could strongly affect soil erosion and the capability of soils to sustain agriculture and in turn impact regional or global food security. The objective of our study was to develop a method to assess soil sustainability to erosion under changes in land use and climate. The method was applied in a typical mixed Mediterranean landscape in a wine-growing watershed (75 km2) within the Languedoc region (La Peyne, France) for two periods: a first period with the current climate and land use and a second period with the climate and land use scenarios at the end of the twenty-first century. The Intergovernmental Panel on Climate Change A1B future rainfall scenarios from the Météo France General circulation model was coupled with four contrasting land use change scenarios that were designed using a spatially-explicit land use change model. Mean annual erosion rate was estimated with an expert-based soil erosion model. Soil life expectancy was assessed using soil depth. Soil erosion rate and soil life expectancy were combined into a sustainability index. The median simulated soil erosion rate for the current period was 3.5 t/ha/year and the soil life expectancy was 273 years, showing a low sustainability of soils. For the future period with the same land use distribution, the median simulated soil erosion rate was 4.2 t/ha/year and the soil life expectancy was 249 years. The results show that soil erosion rate and soil life expectancy are more sensitive to changes in land use than to changes in precipitation. Among the scenarios tested, institution of a mandatory grass cover in vineyards seems to be an efficient means of significantly improving soil sustainability, both in terms of decreased soil erosion rates and increased soil life expectancies.