Modeling vector-borne diseases is best conducted when heterogeneity among interacting biotic and abiotic processes is captured. However, the successful integration of these complex processes is difficult, hindered by a lack of understanding of how these relationships influence disease transmission across varying scales. West Nile virus (WNV) is the most important mosquito-borne disease in the United States. Vectored by Culex mosquitoes and maintained in the environment by avian hosts, the virus can spill over into humans and horses, sometimes causing severe neuroinvasive illness. Several modeling studies have evaluated drivers of WNV disease risk, but nearly all have done so at broad scales and have reported mixed results of the effects of common explanatory variables. As a result, fine-scale relationships with common explanatory variables, particularly climatic, socioeconomic, and human demographic, remain uncertain across varying spatial extents. Using an interdisciplinary approach and an ongoing 12-year study of the Chicago region, this study evaluated the factors explaining WNV disease risk at high spatiotemporal resolution, comparing the human WNV model and covariate performance across three increasing spatial extents: ultrafine, local, and county scales. Our results demonstrate that as spatial extent increased, model performance increased. In addition, only six of the 23 assessed covariates were included in best-fit models of at least two scales. These results suggest that the mechanisms driving WNV ecology are scale-dependent and covariate importance increases as extent decreases. These tools may be particularly helpful for public health, mosquito, and disease control personnel in predicting and preventing disease within local and fine-scale jurisdictions, before spillover occurs.