Natural processes and human activities impact mercury (Hg) pollution in rivers. Investigating the individual contributions and interactions of factors affecting variations in Hg concentrations, particularly under climate change, is crucial for safeguarding watershed ecosystems and human health. We collected 381 water samples from China's Weihe River Basin (WRB) during dry and wet seasons to assess the total Hg (THg) concentration. Results revealed high Hg concentrations in the WRB (0.1–2200.9 ng/L, mean 126.2 ± 335.5 ng/L), with higher levels during the wet season (wet season: 249.1 ± 453.5 ng/L, dry season: 12.7 ± 14.0 ng/L), particularly in the mainstream and southern tributaries of the Weihe River. Industrial pollution (contributing 26.2 %) and precipitation (contributing 33.5 %) drove spatial heterogeneity in THg concentrations during the dry and wet seasons, respectively. Notably, combined explanatory power increased to 47.9 % when interaction was considered, highlighting the amplifying effect of climate change, particularly precipitation, on the impact of industrial pollution. The middle and downstream of the Weihe River, especially the Guanzhong urban agglomeration, were identified as high-risk regions for Hg pollution. With ongoing climate change the risk of Hg exposure in the WRB is expected to escalate. This study lays a robust scientific foundation for the effective management of Hg pollution in analogous river systems worldwide.