To synthesis a series of six chalcones that resemble those occur in nature and to evaluate the in vitro antimicrobial activity of these chalcones against Gram positive and Gram negative bacteria and fungi. Chalcones were synthesized from acetophenone and substituted benzaldehydes via the Claisen-Schmidt condensation and utilizing a green chemistry protocol using sodium carbonate as a catalyst in pure water with excellent yields. The antimicrobial evaluation was performed by filter paper disc plate method against selected microorganisms and using amoxicillin and fluconazole as standards. The structure of the synthesized derivatives has been characterized by elemental microanalysis (CHN), FTIR Spectroscopy, and other physicochemical properties. The antimicrobial evaluation of these synthesized chalcones revealed a promised antimicrobial activity. The ease of the synthesis and purification of these chalcones in addition to the observed high yields make this green protocol the most convenient, operative and environmentally friendly protocol for the synthesis of chalcones by the Claisen-Schmidt condensation. Chalcone derivatives have an excellent promise for further development as commercial antimicrobial agents.