Designing efficient and economical oxygen-evolving catalysts in acid media is of prime importance to develop proton exchange membrane water electrolysis for hydrogen production but still remains a great challenge. Herein, by codoping of nonprecious Cr, W, and Cu elements into the lattice of RuIr-mixed oxide, we construct a high-entropy rutile (Ru0.2Ir0.2Cr0.2W0.2Cu0.2)O2 as a superior catalyst for acidic water oxidation. This oxide exhibits a small overpotential of 220 mV at 10 mA cm–2geo with good stability in acidic electrolyte. Its mass activity reaches up to 1480.9 A g–1noble metal at 1.53 V versus RHE, surpassing most reported Ru-based catalysts. Our microstructural analysis reveals that the multielement doping inhibits the crystalline grains coarsening due to the lattice distortion and hence increases the active surface areas. More interestingly, electronic structure studies demonstrate that these dopants result in a metal–insulator transition, which weakens the Ru–O binding strength and enhances the intrinsic activity of the active sites.