Previous studies found non-linear mutual interactions among hydrometeorological factors on diarrheal disease. However, the complex interactions of the hydrometeorological, topographical and human activity factors need to be further explored. This study aimed to reveal how hydrological and other factors jointly influence bacillary dysentery in different geographical regions. Using Anhui Province in China, consisted of Huaibei plain, Jianghuai hilly and Wannan mountainous regions, we integrated multi-source data (6 meteorological, 3 hydrological, 2 topographic, and 9 socioeconomic variables) to explore the direct and interactive relationship between hydrological factors (quick flow, baseflow and local recharge) and other factors by combining the ecosystem model InVEST with spatial statistical analysis. The results showed hydrological factors had significant impact powers (q = 0.444 (Huaibei plain) for local recharge, 0.412 (Jianghuai hilly region) and 0.891 (Wannan mountainous region) for quick flow, respectively) on bacillary dysentery in different regions, but lost powers at provincial level. Land use and soil properties have created significant interactions with hydrological factors across Anhui province. Particularly, percentage of farmland in Anhui province can influence quick flow across Jianghuai, Wannan regions and the whole province, and it also has significant interactions with the baseflow and local recharge across the plain as well as the whole province. Percentage of urban areas had interactions with baseflow and local recharge in Jianghuai and Wannan regions. Additionally, baseflow and local recharge could be interacted with meteorological factors (e.g. temperature and wind speed), while these interactions varied in different regions. In conclusion, it was evident that hydrological factors had significant impacts on bacillary dysentery, and also interacted significantly with meteorological and socioeconomic factors. This study applying ecosystem model and spatial analysis help reveal the complex and nonlinear transmission of bacillary dysentery in different geographical regions, supporting the development of precise public health interventions with consideration of hydrological factors.