The removal of natural organic matter (NOM), particularly humic substances (HS) from surface waters during drinking water treatment is necessary to avoid various water quality problems in supply, such as the formation of disinfection by-products. As an alternative to conventional processes (e.g. coagulation), and in the light of the rapidly increasing applications of nanozyme in bio-catalysis, a novel Fe–N–C oxidase-like nanozyme (FeNZ) has been prepared and used to catalyze the oxidative degradation of NOM during simple aeration. Using humic acid (HA) as a model NOM it was found that the HA removal (as TOC) was increased by a factor of 6 with a low dose (10 mg/L) of FeNZ compared to an aerated solution without FeNZ. A variety of analytical methods was used to investigate the oxygen reduction reaction, including cyclic voltammetry, electron spin resonance, and density functional theory (DFT) simulation. Based on these studies, a catalytic oxidation mechanism described as “adsorption-activation-oxidation” was proposed. The enhanced NOM removal performance of FeNZ catalytic oxidation was confirmed with samples of natural surface water in terms of organic mineralization and conversion of hydrophobic to hydrophilic components. The results show great potential for the use of oxidase-like nano catalytic materials in the field of water treatment.