The low O2 activation ability at low temperatures and SO2 poisoning are challenges for metal oxide catalysts in the application of Hg0 removal in flue gas. A novel high-entropy fluorite oxide (MgAlMnCo)CeO2 (Co-HEO) with the second phase of spinel is synthesized by the microwave hydrothermal method for the first time. A high efficiency of Hg0 removal (close to 100%) is achieved by Co-HEO catalytic oxidation at temperatures as low as 100 °C and in the atmosphere of 145 μg m-3 Hg0 at a high GHSV (gas hourly space velocity) of 95,000 h-1. According to O2-TPD and in situ FT-IR, this extremely superior catalytic oxidation performance at low temperatures originates from the activation ability of Co-HEO to transform O2 into superoxide and peroxide, which is promoted by point defects induced from the spinel/fluorite heterointerfaces. Meanwhile, SO2 resistance of Co-HEO for Hg0 removal is also improved up to 2000 ppm due to the high-entropy-stabilized structure, construction of heterointerfaces, and synergistic effect of the multicomponents for inhibiting the oxidation of SO2 to surface sulfate. The design strategy of the dual-phase high-entropy material launches a new route for metal oxides in the application of catalytic oxidation and SO2 resistance.