Abstract The emergence of antimicrobial resistance has created an urgent need for the development of novel bioactive molecules. The present study reports the environmentally sustainable synthesis of hydroxyl semicarbazone derivatives derived from substituted diaryl ketones and acetophenones. Green chemistry strategies, particularly microwave-assisted synthesis, were employed to improve reaction efficiency while reducing solvent usage, energy consumption, and reaction time. The synthesized compounds were characterized using elemental analysis, Fourier-transform infrared spectroscopy (FTIR), and proton nuclear magnetic resonance spectroscopy (¹H NMR). Antibacterial activity was evaluated against representative Gram-positive and Gram-negative bacterial strains. Several derivatives demonstrated significant inhibitory activity, highlighting the influence of structural modifications and hydrophilic properties on biological performance. The study demonstrates that green synthetic methodologies can successfully generate biologically relevant semicarbazone derivatives with potential pharmaceutical applications.