A simple and efficient method has been developed for the synthesis of various 2-quinoxalinone-3-hydrazone derivatives using microwave irradiation technique. The series of 2-quinoxalinone-3-hydrazone derivatives synthesized, were structurally confirmed by analytical and spectral data and evaluated for their antimicrobial activities. The results showed that this skeletal framework exhibited marked potency as antimicrobial agents. The most active antibacterial agent was 3-{2-[1-(6-chloro-2-oxo-2H-chromen-3-yl)ethylidene]hydrazinyl}quinoxalin-2(1H)-one, 7 while 3-[2-(propan-2-ylidene)hydrazinyl]quinoxalin-2(1H)-one, 2 appeared to be the most active antifungal agent.