The Three Gorges Reservoir (TGR), China, is the largest man-made reservoir in the world. Harmful algal blooms (HABs) have become common since the reservoir’s impoundment in 2003. To investigate the mechanisms of HAB formation in the reservoir and to determine possible mitigation measures, we conducted surveys over a range of spatial scales and temporal resolutions over a 2-y period (March 2013–December 2014). The large-scale survey (the portion of the reservoir on the main stem of the Yangtze River and 22 tributaries) revealed that cyanobacteria blooms were restricted to the upper reaches of the tributaries. The medium-scale survey (1 tributary: Pengxi River) showed that cyanobacteria blooms were confined to the early-spring period with the initiation of thermal stratification in the deep-water column. The small-scale survey (a local, backwater lake in the Pengxi River), which was of higher-temporal resolution than the other 2 surveys, demonstrated that the bloom occurred at the same time as the formation of a surface-density layer unique to the geomorphology and water-control management of the reservoir. The vertical distributions of the bloom and surface-density layer appeared to be related, although the density layer persisted beyond the duration of the HABs. We hypothesized that limited nutrient diffusion into these density layers could result in nutrient limitation despite the hyper-eutrophic conditions that generally characterize the TGR basin. In the main stem of the Yangtze River and lower reaches of the tributaries in the TGR, algal blooms were not observed because of continuous, deep mixing throughout the year. We conclude that the hydrological stability and geomorphological characteristics of the TGR play critical roles in regulating the temporal and spatial patterns of algal blooms and that artificial mixing of the water column is currently the best option to limit HAB formation, especially in upper tributaries.