Hemorrhagic Fever with Renal Syndrome (HFRS) is a rodent-borne endemic disease caused by Hantavirus, which poses an increasingly serious threat to public health, especially in China. In this country, Shaanxi Province is one of the top regions with the highest HFRS incidence in the past years. It is of great importance to explore the potential influences on the spatiotemporal variations of HFRS epidemics across this province, which would provide useful clues for local authorities making targeted interventions on this disease.The county-level HFRS incidence rates during 2005-2017, as well as some potential natural and socioeconomic variables, were collected and analyzed by using spatial auto-correlation and hot-spot analysis tools as well as a Geodetector tool to explore the spatiotemporal relationships between the incidence rates and the potential variables. The HFRS epidemics in Shaanxi Province were obviously higher than the national level and presented clear temporal fluctuation and spatial clustering at the county scale. More than 90% of the counties with relatively high HFRS incidence rates concentrated in the Guanzhong Plain where obvious spatial heterogeneity was also observed. Some variables including the percentage of plain area and construction land, and population density separately accounted for about 20% of spatial variations of the county-level epidemic across the whole province. By comparison, the spatial pattern of this epidemic in the Guanzhong Plain with no obvious socioeconomic differences was mainly affected by precipitation, normalized difference vegetation index, and land-use types. Thus, the Guanzhong Plain with both spatially clustering higher incidence rates and obviously differentiated natural and socioeconomic conditions was the crucial region of the HFRS prevalence across Shaanxi Province. We suggest that precipitation, vegetation conditions, and land-use types should be heavily considered by local authorities for making effective interventions on this disease across Shaanxi Province, especially in the Guanzhong Plain with relatively high land urbanization and population density.