Buruli Ulcer (BU) is an endemic prevalent disease in Ghana and other West African countries including; Cote d´Ivoire, Benin and Togo. Despite recent upsurge of research in Buruli Ulcer, the natural reservoir and mode of transmission of Mycobacterium ulcerans (MU) have not yet been determined. However, all major foci are found in wetlands of tropical and subtropical countries. In this study, a landscape spatial hydrological modeling approach based on Potential Maximum Soil Water Retention (PMSWR), Soil Conservation Service Curve Number Grid (SCS CNGrid) and empirical evidence from field research were applied to understand their relationship with BU disease in two districts of Ghana. Landuse data, Hydrological Soil Groups (HSGs), Landsat images and Digital Elevation Models (DEMs) were used to generate the SCS CNGrid and the PMSWR of the study areas. The results of the SCS CNGrid and PMSWR maps linked BU endemic areas to low to moderate surface runoff potential and high to moderate PMSWR. BU endemic communities in the two districts were also mostly enclaved by galamsey (illegal) mining activities and farms. This study proved that the PMSWR and SCS CNGrid values are important hydrological parameters to determine surface runoff potential and thus delineate BU disease prone areas.