Taihu Lake is one of the largest freshwater lakes and serves as one essential drinking water source, while subjected to severe Harmful Algal Blooms (HABs). HABs are destructive water issues that directly threaten human health. HAB in freshwater lakes affects the physicochemical properties of water bodies and the compositions of bacterial communities, which could drive the waterborne pathogen profile changes. However, the relationship between HABs and waterborne pathogens remains poorly known. We herein profile the waterborne pathogens during HABs in water samples collected in 12 sampling sites across two bays in Taihu Lake and investigate the effect of HAB on waterborne pathogen profiles. Adopting the Illumina 16S rRNA microbial community profiling approach, potential pathogens including Aeromonas sobria, Legionella spp., Leptospira spp., and Mycobacterium spp. were widely detected in all water samples, with relative abundance ranging from 0.18% to 0.97%. Furthermore, the overall analysis revealed certain environmental bacterial species and abiotic factors were essential factors impacting the pathogen profile. Specifically, a co-occurrence network analysis identified Cyanobium PCC-6307 (the dominant cyanobacteria species in this study) as the central hub, suggesting its significant connections to pathogens including Legionella spp., Leptospira spp., and Mycobacterium spp. Meanwhile, Spearman’s correlation test and Redundancy Analysis (RDA) indicated that nutrient concentrations, especially phosphorus, plays a vital role in pathogen profiles. These results demonstrate that HAB is a potential driver of pathogen proliferation, thus providing a reference for further prevention and control of pathogens in natural water bodies.