A new series of 3-chloro-6-methylbenzo[b]-thiophene-2-carbonylamino acid methyl ester, hydrazide and their corresponding hydrazone derivatives have been synthesized as potential antibacterial agents. Most of the compounds described herein (II-XXXV) have been derived from one key intermediate namely 3-chloro-6-methylbenzo[b]-thiophene-2-carbonyl chloride (I), and their structures were confirmed by IR, 1H-NMR, MS spectral and elemental analysis. The antibacterial activities of of some of the synthesized compounds were studied against Grampositive bacteria; Staphylococcus aureus, Bacillus subtilis, and Gram-negative bacteria; Escherichia coli, and Pseudomonas aeruginosa by using filter paper disc method. In this paper, the structure-activity relationships (SAR) of our synthetic compounds were discussed.