The unique geological conditions of karst regions create highly heterogeneous habitat characteristics, and the addition of human disturbance results in rocky desertification. Water and soil loss are the core questions, and moreover, runoff is the key factor in this process. To further investigate these problems, a typical karst peak cluster depression in southwestern China was selected for this study. Based on the optimal simulation of the runoff yield and flow in this area, the factor detectors and interaction detectors in the geographical detector method were used to quantitatively analyze the factors influencing runoff and their interactions for different geomorphic types. The results show that: (1) the three main factors influencing the total river runoff, surface runoff, and groundwater are landscape fragmentation, land use type, and precipitation, but the ranking of these main influencing factors in each geomorphic type region exists different; (2) the dominant factor in the relatively higher elevation regions is precipitation; (3) the interaction detector results reveal that the interactions between factors enhance the overall influence of a single factor on the runoff generation in all of the geomorphic type regions, including two interaction types of nonlinear enhancement and bifactor enhancement; and (4) the interactions between the factors in the middle elevation plain, middle elevation terrace, and middle relief mountain regions are stronger than those in the middle elevation hill and small relief mountain regions. Quantitative analysis of the factors influencing runoff in karst areas cannot only promote optimization of the water and soil services, but it also provides a scientific basis for improving the comprehensive treatment of rocky desertification.