Tumor microenvironment (TME)‐responsive nanozymes‐based catalytic therapy shows great potential in combating malignant tumor. However, their biological application still suffers from deficient catalytic activity. Herein, the MoOx‐Rh metallene nanozyme demonstrates highly efficient multiple enzymatic catalytic activities, where MoOx species atomically dispersed on Rh metallene surface. The resulting structures enable MoOx‐Rh metallene with maximally exposed active oxide‐metallene interface and more atoms sites around interface can be well finely regulated. Results of experiment and density functional theory (DFT) simulations support the notion that atomic interface structure facilitates multiple enzyme‐like reactions. As a TME‐responsive nanozyme, MoOx‐Rh metallene exhibits remarkable therapeutic effect of tumor due to intrinsic near‐infrared photothermal effect and laser‐enhanced multiple enzymatic catalytic activities. This study illustrates the great promise of atomic interface engineering strategy in tumor catalytic therapy.