With an intention to synergize the anti-bacterial activity of chalcones and rhodanine-3-acetic acid, several hybrid compounds possessing chalcone and rhodanine-3-acetic acid moieties were synthesized and tested for their anti-bacterial activity. Some compounds presented great anti-microbial activities against Gram-positive bacteria (including the multidrug-resistant clinical isolates). This class of compounds presented high potency against Staphylococcus aureus, among which the derivatives 5k with a MIC of 2 μg/mL was as active as the standard drug (norfloxacin) and less active than oxacillin. Compounds 5a-s did not inhibit the growth of Gram-negative bacteria Escherichia coli CCARM 1924 or E. coli CCARM 1356 at 64 μg/mL.