Antibiotic resistance is a major health problem; so there is a emerging need for developing new antibiotic agents. A novel series of (6-methoxy-2-naphthyl) propanamide derivatives were synthesized and evaluated for their potential antibacterial activity. The minimum inhibitory concentration of these compounds were determined by microdilution technique against five known strains of bacteria. Test strains included three Gram-positive strains (Streptococcus pneumonia, Bacillus subtilis and Staphylococcus aureus) and two Gram-negative strains (Escherichia coli and Salmonella typhimurium). According to the observed antibacterial activity results showed that compounds N-(4-(2-(5-bromo-2-hydroxybenzylidene)hydrazine carbonyl) phenyl)-2-(6-meth oxynaphthalen-2-yl)propanamide 2d and N-(4-(2-(2,4-dichlorobenzylidene)hydrazine carbonyl)phenyl)-2-(6-methoxy-naphthalen-2-yl)propanamide 2j has potent antibacterial activity against B. subtilis (minimal inhibitory concentrations 1.95 µg/ml). Also 2-(6-methoxynaphthalen-2-yl)-N-(4-(2-(4-oxopentan-2-ylidene)hydrazinecarbonnyl)phenyl) propanamide 6 showed potent antibacterial activity against S. pneumonia (minimal inhibitory concentrations 1.95 µg/ml) compared to Naproxen (7.81, 15.63 µg/ml) and the reference drug Ampicillin (7.81 µg/ml). Two of the synthesized compounds, namely, 2j and 2k exhibited more potent antibacterial activity than the reference drugs (Gentamicin and Ampicillin) against all the test strains of bacteria. Molecular docking simulation was also carried out for Enoyl-aceyl carrier protein reductase enzyme, which is responsible for catalyzing the final step of bacterial fatty acid biosynthesis and is an attractive target for the development of novel antibacterial agents. In addition, generation of 3D pharmacophore model and quantitative structure–activity relationship models were combined to explore the structural requirements controlling the observed antibacterial properties.