The escalating dissemination of antibiotic resistance genes (ARGs) in lake ecosystems has drawn substantial attention regarding their potential risks to public health. However, the spatiotemporal patterns and the driving mechanisms of ARGs within lake ecosystems under anthropogenic activities remain incompletely understood. Here, 132 sediment and 132 water samples were collected from the production and living, tourism, and natural areas of Baiyangdian Lake during the dry and wet seasons. The findings showed that the total ARGs abundance in sediments during the dry season was 4.37 to 19.05 times higher than that in the wet season. Conversely, the total ARGs abundance in water was 1.97 to 12.51 times greater in the wet season as compared to the dry season. Notably, the production and living area and the tourism area exhibited significantly higher ARGs abundances in both sediments and water than the natural area. Specifically, 23 and 11 types of potential pathogenic bacteria were identified in sediments and water, respectively, with the abundance of animal-origin pathogenic bacteria reaching up to 4.55%. Network analysis revealed that dominant phyla, including Proteobacteria, Bacteroidota, and Chloroflexi, were potential major hosts of ARGs. Additionally, the intI1 gene significantly correlated with ARGs, indicating its crucial role in the dissemination of ARGs. PLS-PM further demonstrated that biotic factors (intI1 gene, bacterial abundance) and abiotic factors (TN, TP) were crucial for ARG spatiotemporal distribution. Overall, our work provided insights into the impacts of anthropogenic activities on ARGs and pinpointed potential high-risk areas, providing crucial implications for the management of ARGs contamination.