Heavy metal (HM) contamination of aquatic ecosystems has increasingly posed threats to ecological balance and health. Analysis of sediments to determine water pollution sources is widely reported, while quantitative research about the effects of environmental factors on the distribution of HMs and relevant microbial communities is limited. Here, we investigated 6 kinds of HM pollution characteristics (As, Cd, Cr, Cu, Pb, and Zn) of the Pearl River Delta (PRD) by collecting surface sediment samples around the main stream and estuary and explored the influencing factors with a geographical detector method (GDM). The shifts in the corresponding microbial community was further analyzed, and the influence mechanism was clearly elucidated using partial least squares path modeling (PLS-PM). Results showed that (i) most HM contents of the sediments greatly exceeded the local background values, wherein, Cd had the highest pollution level; (ii) temperature was considered the dominant natural factor of HM distribution, except for Pb, with an influence degree of 0.68–0.97; (iii) industrial activity is an significant anthropogenic factor for HM distribution, and the electroplating industry was the main source for Cr, Cu and Zn; (iv) the network analysis revealed that As, Cu and Cr were enriched in some HM-tolerant bacteria (mainly Chloroflexi, Acidobacteriota and Proteobacteria), while heavy Cd pollution induced a reduction in sensitive bacterial taxa; (v) PLS-PM demonstrated that human activities largely affect bacterial communities by causing HM pollution. This study could provide guidance for better management of HM pollution control practices, such as specific industrial governance and layout optimization.