A thorough understanding of the complex response of hydrologic processes to latent factors is of great significance for regional soil erosion and water resources management. However, what kind of mediation effect exists between hydrologic processes and latent factors is not yet clear, especially in heterogeneous karst regions. In this study, the elasticity coefficient method and partial least squares structural equation modelling (PLS‐SEM) were used to investigate the mechanism of latent factors on hydrologic processes in karst basins and to explore the mediation effect between latent factors and hydrologic processes. The results show that the runoff of Yeji River Basin decreased during 1997–2004, but increased or stabilized since 2005. On the monthly scale, the runoff in July and December showed an ‘inverted V‐shaped’ change. Both elasticity coefficient method and PLS‐SEM showed that climate change contributed the most to runoff (direct effect accounted for 37.94% ~ 61.41%). In PLS‐SEM, the total effect sizes of latent factors on runoff were as follows: climate change (0.751 ~ 0.963) > vegetation (0.296 ~ 0.740) > karst characteristics factors (KCF) (−0.454 ~ −0.563) > human activities (−0.036 ~ −0.528) > land use and cover change (LUCC) (−0.036 ~ −0.205). In the typical karst basin, two mediation pathways have been determined: human activities‐vegetation/LUCC‐runoff, where vegetation and LUCC had a mediation effect of relationships between human activities and runoff; climate change‐KCF‐runoff, where KCF had a mediation effect of relationships between climate change and runoff. Moreover, PLS‐SEM is a preferred method to decouple the complex responses of hydrologic processes in heterogeneous karst basins to climate change and human activities than the elasticity coefficient method. This study conducted further research and exploration on the mechanism of hydrologic processes in heterogeneous karst basins, and provided valuable theoretical references for grassroots water managers to cope with water resources management under the context of future climate change.