Background: Schiff bases are excellent compounds. They were synthesized by condensation of active carbonyl and amines. They were widely used as a substrate in the preparation of industrial compounds as well as pharmaceutical purposes. They exhibit a wide range of biological activities. In this study, based on the importance of Schiff bases, a sustainable synthetic method was developed employing reflux and microwave irradiation.Objective: The aim is to develop a new synthetic method for imidazole Schiff base derivatives synthesis employing reflux, microwave irradiation, and ethanol as a green solvent. Methods: Synthesis of imidazole Schiff base derivatives was carried out under reflux and microwave irradiation conditions. Antibacterial activity of imidazole derivatives and standard drugs was examined against two Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis) and two Gramnegative bacteria (Proteus mirabilis, Escherichia coli). Results: Schiff bases were synthesized in the presence of microwave irradiation and ethanol in high yields 90-98% for 2-4 min. The antibacterial effects of Schiff bases were evaluated against both strains of Gram-positive and Gram-negative. Conclusion: In this paper, a novel series of imidazole Schiff base derivatives were synthesized using reflux, microwave irradiation, and ethanol. Antibacterial effects were investigated. The excellent advantages of microwave irradiation in the synthesis of imidazole derivatives include reduction of reaction time from an hour to a minute, high product yield. In this study, the measurement of antibacterial activity was also important. Imidazole derivatives with Cl, OH, and CH3 groups showed antibacterial effects.