While many studies investigate animal-related risk factors for disease, few have considered environmental or spatial risk factors in the dynamics of bovine tuberculosis (bTB) and brucellosis. In the Ruaha ecosystem of Tanzania, we investigated the role of household location as a predictor for infection with Mycobacterium bovis and exposure to Brucella in pastoralist and agropastoralist cattle herds in a typical African wildlife-livestock-human interface. ArcGIS was utilized to calculate Euclidian distances between households and the nearest river, village center, protected area, and other infected households, followed by multivariate logistic regression to assess the association between risk factors and herd-level bTB and Brucella outcomes. Global and local spatial clustering of bTB-infected and Brucella-exposed herds was explored using the Cuzick-Edward’s test and SaTScan spatial scan statistics. Households located farther from rivers and closer to village centers and herds belonging to agropastoralists were more likely to have bTB-positive cattle. Risk of Brucella exposure increased with proximity to protected areas. One spatial cluster of households with Brucella spp. seropositive cattle was identified. Spatial factors may be useful for assessing disease risk and for formulating intervention and control strategies for households that manage cattle in ecosystems characterized by seasonally limited resources and intense wildlife-livestock interfaces.