This study evaluated the impact of oxygenation on the accumulation of methylmercury (MeHg), total mercury (Hg), iron (Fe), and manganese (Mn) in the anoxic hypolimnion of North Twin Lake, Washington (mean depth = 9.7 m). Within 8 hours of the start of the oxygenation test, mean hypolimnetic total Fe dropped from 833 to 243 μg/L (58% dissolved), and Mn decreased from 119 to 32 μg/L (100% dissolved). After 17 days of oxygenation, mean hypolimnetic total Hg decreased from 0.77 to 0.58 ng/L, and MeHg decreased from 0.20 to 0.10 ng/L. A month after the end of the oxygenation test, MeHg, total Hg, Fe, and Mn concentrations rebounded to pre-oxygenation levels. Metal dynamics were explained by the differing redox characteristics of Fe (fast oxidation kinetics; reduction at lower redox potential) and Mn (slow oxidation kinetics; reduction at higher redox potential) in natural waters, and the tendency for Fe oxides to co-precipitate with reduced Mn, ionic Hg, and MeHg. From a lake management perspective, the study highlights the role that oxidized metals in surfacial sediments play in retaining Hg in profundal sediments and suggests that sorption characteristics of metal oxides could be exploited to manage Hg bioaccumulation in aquatic biota. The study also suggests that for oxygenation to effectively repress the accumulation of redox-sensitive compounds in the hypolimnion, oxygenation systems should (1) start before anoxic conditions are established; (2) operate continuously through the entire stratified season; and (3) maintain oxygen levels at the sediment–water interface to ensure oxygen penetration into surfacial sediments.