ABSTRACT The Pra River Basin in Ghana is a major source of ecological, cultural, and economic benefits. However, it has been experiencing degradation, and logistical constraints have limited the implementation of Integrated Water Resources Management. This study presents a GIS-based ecohydrological risk model that identifies ecohydrological units with the highest degradation risk. First, the PRB was divided into 25 eco-hydrological units. Second, seven drivers of degradation were identified and mapped. The drivers were reclassified into five categories with risk scores of 1–5, with 5 indicating higher risk scores. The variables were ranked using the Analytical Hierarchy Process, the degradation risk model was calculated using the weighted sum method, and the multi-criteria decision tool was used to identify the ecohydrological units with the highest degradation risk. Of the 25 ecohydrological units delineated, the Buama, Lower Offin, Ayensu, and Oda ecohydrological units were found to be at the highest risk of degradation due to high artisanal small-scale gold mining, high population density, low forest/vegetation cover, and high encroachment in waterways. The results can be used as a guide to prioritize management intervention, starting with the areas classified as high risk and moving down to those classified as moderate risk.