Acquiring the detailed reaction mechanism between halogenated quinones and hydroxamic acids is crucial for better understanding of the potential applications of benzohydroxamic acids in the detoxification of the carcinogenic polyhalogenated quinoid metabolites of pentachlorophenol. In this study, the reaction mechanism between tetrachloro-o-benzoquinone (o-TCBQ) and N-methyl benzohydroxamic acid (N-MeBHA) has been systematically investigated at the B3LYP/6-311++G(d,p) level. It was found that o-TCBQ can react with the anion of N-MeBHA (N-MeBHA⁻) under mild conditions. As the first step of reaction, a molecular complex is formed between o-TCBQ and N-MeBHA⁻ followed by the nucleophilic attack of the O atom of N-MeBHA⁻ at the C atom attached to the Cl atom of o-TCBQ, resulting in the formation of an unstable intermediate containing an N–O bond. Subsequently, the unstable intermediate decomposes via the homolytic cleavage of the N–O bond to produce N-centered and O-centered radicals. For the O-centered radical, it can isomerize to a C-centered form upon structural relaxation. Finally, these radicals react with each other to form the major C–N bonding products and minor C–O bonding products. In addition, it was found that the reactivity of o-TCBQ with N-MeBHA is higher than that of tetrachloro-p-benzoquinone (p-TCBQ).