With the extensive development of nanozymes in recent years, catalytic efficiency has been considered as the Gordian knot that restricts the further applications of nanozyme. Moreover, the usage of layered double hydroxides (LDHs) as antioxidant nanozymes for scavenging reactive oxygen species (ROS) has not been studied. Herein, we report a vacancies-rich monolayer cobalt-alumina LDH nanosheet (m-CoAl-LDH) through a facile direct synthesis method as an efficient nanozyme with superoxide dismutase (SOD)-like activity. The m-CoAl-LDH exhibits a record-breaking catalytic efficiency with the catalytic constant (K_cat) as high as 4.33 × 10¹¹ M⁻¹·s⁻¹. Elucidated by the experimental and theoretical studies, the abundant oxygen and metal vacancies were existed in the single layer for the outstanding performance owing to the increased active sites. In addition, density functional theory (DFT) calculations further reveal the significant role of synergistic effect of oxygen and metal vacancies in reducing the adsorption energy of superoxide (O₂^•−), which improves the catalytic performance. The m-CoAl-LDH nanosheets were applied in cells to relieving the oxidative damage caused by O₂^•− in mitochondria. Such vacancy-rich monolayer CoAl-LDH nanosheets represent the first example of LDH nanozyme with specific SOD-like activity as well as record high catalytic efficiency, which may provide deeper insight into efficient nanozyme design by defect-engineering.