Harmful algal blooms of the cyanobacterium Microcystis spp. have become increasingly pervasive in the San Francisco Estuary Delta (California, USA) since the early 2000's and their rise has coincided with a substantial decrease in several important fish species. It is likely that the fish decline is driven by multiple stressors, we sought to investigate direct and indirect effects Microcystis blooms may have on the Delta food web. The Microcystis population was tracked for two years throughout six sites in the Delta using quantitative PCR. A suite of physicochemical parameters were compared across the six sites and revealed an increased probability of Microcystis enrichment in locations with high conductivity–a proxy for water residence time. High throughput amplicon sequencing and colony PCR sequencing revealed the presence of 10 different strains of Microcystis, including six different microcystin-producing genotypes. In addition to the microcystin operon, shotgun metagenomic analysis identified a variety of Microcystis secondary metabolite pathways, including: aeruginosin, cyanopeptolin, microginin, microviridin j and piricyclamide. Based on rarefaction analysis and estimates of Shannon diversity (H'), we observed a sizable reduction in microbial community diversity during a large Microcystis bloom (H'=0.61) relative to periods preceding (H'=2.32) or following (H'=3.71) the bloom. Physicochemical conditions of the water column were stable throughout the bloom period, suggesting a possible role of broad allelopathy influencing microbial food web structure during the bloom. Co-occurrence (network) analysis was employed to elucidate synergistic and antagonistic relationships between Microcystis and other bacteria.