Abstract Mimicking the structure of natural enzyme active sites offers a promising strategy for the rational design of nanozymes. However, this biomimetic approach predominantly focuses on replicating the configuration of the metal active center in natural enzymes, often overlooking the critical influence of the catalytic site's microenvironment. Here, inspired by the active center and coordination microenvironment of natural organophosphorus hydrolase (OPH), Ce 2 O 2 CN 2 /NC, a novel cerium‐based nanozyme is first reported to mimic OPH. In Ce 2 O 2 CN 2 /NC, Ce species serve as active sites, while the adjacent N site ([N═C═N] 2− ) functions as a general base, mimicking histidine in natural enzymes to facilitate the hydrolysis process. Using paraoxon as a model target, Ce 2 O 2 CN 2 /NC demonstrates rapid dephosphorylation of phosphotriester across a wide range of temperatures and pH values, significantly outperforming natural OPH and CeO 2 nanoparticles. The systematic experiments and theoretical calculations reveal the underlying mechanisms responsible for the enhanced OPH‐mimicking performance. Capitalizing on its phosphatase‐like activity, Ce 2 O 2 CN 2 /NC nanozyme is successfully employed to develop a colorimetric biosensor for the rapid and selective detection of organophosphorus pesticides. This study holds great promise in developing efficient nanozymes and broadens the range of Ce‐based nanozymes.