Lake-reservoir type water sources are crucial to China’s water supply, playing a vital role in ensuring regional water security. This study focused on the Panjiakou Reservoir, a key water source for the Luanhe-Tianjin Water Diversion Project. A three-dimensional numerical model was performed to unveil the response of bottom hypoxia under varying reservoir operations and nitrate concentrations in the inflow. Based on these findings, we proposed comprehensive strategies for preventing and controlling bottom hypoxia. In this paper, the measured reservoir data from 2017 to 2018 were used to verify the reliability of the model. Results show that increasing the reservoir"s outflow significantly shortened the duration of bottom hypoxia and weakened its severity in the later stage of thermal stratification. Moreover, a substantial reduction in the nitrate concentration in the inflow resulted in a significant increase in the duration, severity, and spatial extent of bottom hypoxia. Based on the actual operation of the reservoir and the requirements for meeting the standards of water supply quality, this article suggests: 1) joint scheduling with the downstream Daheiting Reservoir should be implemented, adjusting the outflow volumes during January-April and September-December to concentrate the discharge in mid-to-late October. This optimization reduced the duration of severe hypoxia and the maximum hypoxic area by 54% and 23%, respectively. 2) Second, we recommended reducing the upstream nitrate concentration to 1.5-2 mg/L as part of the watershed pollution control efforts. This approach ensured that the total nitrogen (TN) concentration in the discharged water satisfied the standards, while maximizing the mitigating effect of nitrate on bottom hypoxia. Our study proposed a comprehensive strategy for reservoir water quality protection from multiple perspectives, including "upstream pollution source concentration control, reservoir hypoxia prevention, and downstream water quality standards compliance", which were of importance for the protection and restoration of aquatic environments in the deep water source reservoirs.