Hongfeng Lake is one of the largest artificial freshwater lakes on the Karst plateau of China, and the control of external nutrient input into the lake by a vegetation buffer zone is key to mitigating its eutrophication. Although soil microbial communities play key roles in nitrogen pollutant interception and in maintaining ecosystem stability, few studies have investigated these communities in lake vegetation buffer zone soils. In this study, the effects of seasonal and human disturbances on soil microbial communities of the vegetation buffer zones of Hongfeng Lake were determined by high-throughput sequencing and community profiling. BIOENV analysis revealed that soil redox potential was the primary factor associated with soil microbial community composition during the wet season, while Total nitrogen better explained variation in the dry season microbial communities. The relative abundances of Cyanobacteria were significantly higher in vegetation buffer zone soils that were polluted by upstream livestock and domestic sewage. Further, analysis of microbial community network topological features indicated that the soil microbial communities of the vegetation buffer zone markedly differed between wet and dry seasons. Specifically, wet season community networks suggested that the proliferation of Cyanobacteria, E. coli, and Panaeolus papilionaceus inhibited the growth of microorganisms capable of nitrification and denitrification, thereby contributing to increased risk of nitrogen loss to surface waters. Based on these results, we suggest that discharge of domestic sewage and livestock wastewater should be prohibited along Hongfeng Lake tributaries. Moreover, vegetation should be artificially managed to improve the mitigation of non-point source pollution into the lake via vegetation buffer zones.