Climate change and land use change are the two main factors affecting the regional water cycle and water resources management. However, runoff studies in the karst basin based on future scenario projections are still lacking. To fill this gap, this study proposes a framework consisting of a future land use simulation model (FLUS), an automated statistical downscaling model (ASD), a soil and water assessment tool (SWAT) and a multi-point calibration strategy. This frameword was used to investigate runoff changes under future climate and land use changes in karst watersheds. The Chengbi River basin, a typical karst region in southwest China, was selected as the study area. The ASD method was developed for climate change projections based on the CanESM5 climate model. Future land use scenarios were projected using the FLUS model and historical land use data. Finally, the SWAT model was calibrated using a multi-site calibration strategy and was used to predict future runoff from 2025–2100. The results show that: (1) the developed SWAT model obtained a Nash efficiency coefficient of 0.83, which can adequately capture the spatial heterogeneity characteristics of karst hydro-climate; (2) land use changes significantly in all three future scenarios, with the main phenomena being the interconversion of farmland and grassland in SSPs1-2.6, the interconversion of grassland, farmland and artificial surfaces in SSPs2-4.5 and the interconversion of woodland, grassland and artificial surfaces in SSPs5-8.5; (3) the average annual temperature will show an upward trend in the future, and the average annual precipitation will increase by 11.53–14.43% and (4) the future annual runoff will show a significant upward trend, with monthly runoff mainly concentrated in July–September. The variability and uncertainty of future runoff during the main-flood period may increase compared to the historical situation. The findings will benefit future water resources management and water security in the karst basin.