Background <p>Hemorrhagic fever with renal syndrome (HFRS) poses a significant public health concern in China. However, the spatiotemporal patterns and underlying drivers of its transmission are not fully understood. This study aims to investigate spatiotemporal heterogeneity of HFRS incidence at the city level and explore its potential influencing factors.</p> Methods <p>Joinpoint regression was utilized to analyze city-level HFRS incidence data (<i>n</i> = 314 cities, 2005–2021) collected from the National Infectious Disease Surveillance System. Furthermore, we employed the Geodetector method to identify the potential driving factors from a set of meteorological, vegetation, and urbanization variables.</p> Results <p>The results from Joinpoint regression analysis revealed an overall declining trend in city-level HFRS incidence across China from 2005 to 2021. Of the cities analyzed, 126 showed an upward trend [the average annual percent change,(AAPC) &gt; 0], 176 a downward trend (AAPC &lt; 0), and 12 remained stable (AAPC = 0). Notably, upward-trend cities were predominantly concentrated in South China. Geodetector analysis indicated that selected climatic and vegetation factors accounted for 19–56% of the spatiotemporal heterogeneity in HFRS incidence, whereas urbanization factors explained only 3–5%. However, synergistic interactions between temperature and urbanization-related variables (i.e., land-use, economic, and demographic dimensions) significantly enhanced their explanatory power, particularly in upward-trend cities, where the combinations increased explanatory capacity by 124–184%.</p> Conclusion <p>In summary, while climatic and vegetation factors remain the primary drivers of the spatiotemporal heterogeneity of HFRS epidemics in China, urbanization also exerts non-negligible influence on city-level incidence. This research offers valuable insights for public health authorities to strengthen their intervention capabilities against this disease.</p> Graphical Abstract <p></p>