The byproducts of anaerobic biogeochemical processes, many mediated at the sediment–water interface, can degrade water quality in the bottom of reservoirs. Using both experimental sediment–water chambers and field monitoring, this study assessed nutrient and metals cycling in the profundal zone of hypereutrophic Hodges Reservoir, San Diego (maximum depth = 29.1 m; maximum surface area = 6.0 km2 ). A focus of the study was methylmercury (MeHg), a toxic form of mercury that bioaccumulates in aquatic food webs. Results confirmed that oxic conditions repressed release of redox-sensitive compounds (e.g., MeHg, ammonia, phosphate, manganese) from profundal sediment, though high sediment oxygen demand complicated experimental efforts to maintain a well-oxygenated sediment–water interface. In both experimental chambers and in the reservoir, patterns of MeHg cycling correlated with manganese cycling, suggesting that moderately low redox conditions that stimulate reductive dissolution of manganese also enhance net Hg methylation. Sediment MeHg flux was tightly coupled with sulfate uptake under moderately reduced conditions, reinforcing the link between sulfate-reducing bacteria and Hg methylation. Results highlight the fact that hypolimnetic oxygenation in Hodges Reservoir using pure oxygen gas, which is planned for spring 2020, must maintain high oxygen concentrations at the profundal sediment–water interface. In addition, results indicate that the presence of manganese in surface water can be used as an indicator of oxygenation’s effectiveness in lowering rates of internal nutrient and MeHg loading.