Enzyme-mediated dephosphorylation reaction is the important approach to realize the inactivation and detection of hazardous phosphate chemicals. To date, many phosphatases-like nanozymes (e.g., CeO) have demonstrated the catalytic hydrolysis ability of the phosphomonoesters, rather than phosphotriester, and the CeO nanozyme only work under relatively harsh conditions of high temperature, and large dosage. Thus, exploration of efficient nanozymes for the rapid dephosphorylation of phosphotriester under mild conditions remains a challenge. Here, a novel CeO@NC nanozyme is developed with excellent phosphatases-like activity based on substrate synergistic effect, in which, CeO nanoparticles embedded in N-doped carbon (NC) material. Taking paraoxon as the model substrate, such CeO@NC nanozyme can drive rapid dephosphorylation of phosphotriester over a broad temperature range, which not only significantly outperforms natural phosphatases and neat CeO, but also can preserve >80% of the optimal activity after exposure of harsh conditions, such as strong acidic/basic medium, high temperature of up to 80 °C. The excellent catalytic performance could be due to that Ce(IV)/Ce(III) species act as the active sites to realize the polarization and hydrolysis of P-O bond while NC template works as the synergistic group to adsorb the substrate. Furthermore, a simple colorimetric assay is developed for the rapid and selective detection of paraoxon. Overall, this work not only develops a highly efficient phosphatases-like nanozyme via substrate synergetic strategy, but also opens an interesting avenue for the rapid detection of organophosphorus pesticides.