Herein, we report the first chiral nanozyme with higher activity than the natural enzyme, which is designed based on mimicking a natural enzyme and the superior structure of covalent organic framework (COF) materials. The well-dispersed iron porphyrin and L-histidine (L-His) units endow the COF nanozyme with high activity. The incorporation of L-His units also imbues the COF nanozyme with selectivity for L-dopa in the oxidation of dopa enantiomers with a selectivity factor up to 1.86, while replacing L-His with D-His can reverse the preference to D-dopa with a selectivity factor of 1.51. The activity and selectivity of the COF nanozyme can be optimized by varying the L-His content which can change the activation energy of the catalytic reactions and the substrate binding.