AbstractAs advanced oxidation processes (AOPs) is considered to be a highly effective approach for degrading organic pollutants, the simultaneous coagulation and oxidation process by the Fenton‐like reaction of nanoscale zero‐valent iron (NZVI) and hydrogen peroxide (H2O2) is investigated to eliminate the harmful cyanobacterium Microcystis aeruginosa in this study, and the process conditions are optimized using the central composite design of response surface methodology (RSM); in addition, the removal efficiency of M. aeruginosa (in terms of chlorophyll a, Chl a) and the verifications of the antioxidant abilities, as well as extracellular organic matters (EOM) and intracellular organic matters (IOM) are investigated under the optimized conditions. Results indicate that H2O2 concentration is the key factor affecting the Chl a removal efficiency, and the maximum Chl a removal reaches 98.10% under the optimized conditions: NZVI concentration 62.82 mg L−1, H2O2 concentration 54.2 mmol L−1, pH 4.38 and rotating speed 67 rpm. The high correlation coefficient (R2 > 0.80) of analysis of variance (ANOVA) demonstrates the RSM model is extremely significant and suitable for experimental results. Moreover, the total organic carbon (TOC) and fluorescent substances (soluble cyanobacteria metabolic byproducts, aromatic proteins II, humic and fulvic acid‐like compounds) for both EOM and IOM are enhanced removal. It is speculated the removal mechanisms of the Fenton‐like process of NZVI/H2O2 for cyanobacterium belongs to the combined actions of the oxidation of Fe(II)/H2O2 and the coagulation of Fe(III), which destroy the defense system and result in the removal of M. aeruginosa.