Industrial chemical processes require sulfur-resistant catalysts, which reduce catalyst replacement costs and simplify process operations. Herein, a high-entropy-stabilized strategy was put forward for sulfur-resistant catalysis. A high entropy (Zn0.2Mg0.2Cu0.2Mn0.2Co0.2Al2O4) showed stable performance in CO oxidation with SO2, while unitary oxide and binary spinel oxide were all deactivated. The mechanism study showed that the adsorption of SO2 onto Zn0.2Mg0.2Cu0.2Mn0.2Co0.2Al2O4 was challenging. Moreover, Zn0.2Mg0.2Cu0.2Mn0.2Co0.2Al2O4 has a high degree of disorder, with five metal elements co-temporarily living in one cell location as cations. Thermodynamic equilibrium allows the sacrificial cations to capture the trace SO2 anchor on the Zn0.2Mg0.2Cu0.2Mn0.2Co0.2Al2O4 surface in time to protect the catalytically active cation. This work reveals the significance of high-entropy structures in sulfur resistance and offers a novel design strategy for sulfur-resistant catalysts.