Lakes and reservoirs globally produce large quantities of methane and carbon dioxide in their sediments, which accumulate in the hypolimnia (bottom waters) during thermally stratified conditions. A key parameter controlling hypolimnetic greenhouse gas concentrations is dissolved oxygen. Land use and climate change have increased hypolimnetic anoxia worldwide in lakes and reservoirs, which is expected to affect their methane and carbon dioxide concentrations. We conducted whole-ecosystem oxygenation experiments to assess the effects of oxygen concentrations on dissolved hypolimnetic greenhouse gas concentrations in comparison to a reference reservoir and calculated the maximum hypolimnetic global warming potential in both reservoirs over three summers. We observed significantly greater hypolimnetic methane under anoxic conditions but similar carbon dioxide concentrations, leading to greater hypolimnetic global warming potential of anoxic hypolimnia. Our study indicates that the global warming potential of hypolimnetic greenhouse gas concentrations may increase as the prevalence of hypolimnetic anoxia increases due to global change.