Based on the structure-activity relationship and active substructure combination, a novel class of substituted 2-phenyl-2-cyclohexanedione enol ester derivatives was designed for use as potential herbicide safeners. A microwave-assisted synthetic route was developed for the substituted 2-phenyl-2-cyclohexenone enol ester derivatives via coupling and acylation reactions. In the modified protocol, the reactions were performed under microwave irradiation, resulting in significant improvements in the yields and reaction times. All of the structures were characterized using IR, 1H NMR, 13C NMR and HRMS spectroscopies. The bioassay results demonstrated that most of these compounds could alleviate clethodim injury to maize. Molecular docking modeling showed that the potential antagonism between compound 3(S24) and clethodim plays a key role in the metabolism of herbicides. This paper presents a new safener candidate for maize protection.