Reservoirs play a crucial role in the drinking water supply for solving the uneven distribution of water resources. Reservoir bays, which serve as direct source areas and initial collection areas of pollutants, are crucial areas for drinking water safety. Systematic observations of heavy metal pollution in reservoir bays are required and urgent under different hydrological regulation. Water samples were collected from 65 bays in the Danjiangkou Reservoir which is the water source of the world’s longest trans-basin water diversion project during the storage and flood discharge period from 2015 to 2019. We investigated the temporal and spatial variation in eight dissolved heavy metals, chromium (Cr), manganese (Mn), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), cadmium (Cd), and lead (Pb), and assessed their human health risks. The driving factors of high-risk metals were identified by constructing a structural equation model (SEM). The results showed that the concentrations of heavy metals decreased after 5 years of reservoir operation and varied significantly (p < 0.05) between the storage period and flood discharge period. The concentrations of Cr, Mn, Cd and Pb were higher in the storage period, but the other four metals (Ni, Cu, Zn, As) had the reverse trend. Notably, the As, Mn, and Pb in individual bays exceeded the water quality standard threshold. The human health risk assessment indicated that only As posed a potential carcinogenic risk (1.29E-04) in the flood discharge period. Land use and water physicochemical properties were the main factors affecting As concentrations, and they explained 32% and 44% of the variability of As in the storage and flood discharge periods, respectively. This study provided critical insights into the periodic dynamics and driving factors of the concentration of heavy metals in reservoir bays, and formulated effective management measures for water quality management.