The intractable emergence of bacterial resistance worldwide urges the need for developing new effective antimicrobial agents to face such virulent strains. Based on the reported effectiveness of both chalcones and benzimidazoles on different bacterial strains including MRSA (Methicillin Resistant Staphylococcus aureus), a hybridization strategy to design a scaffold comprising both moieties was achieved and series of novel chalcone-benzimidazole based compounds were synthesized and tested for their antimicrobial activity. This was performed against Staphylococcus aureus as a representative of Gram positive bacteria and Escherichia coli representing Gram negative bacteria. The satisfactory activity shown against Staphylococcus aureus was a great promoter to test the compounds versus linezolid-resistant MRSA. Promising antimicrobial activity against MRSA was observed for three compounds 3b, 3c and 3e where compound 3e is the most active showing MIC of 3.05 mg/ml. Modest chemical modification revealed a great difference in the activity profile which is intriguing to accomplish further modifications.