Methicillin resistant Staphylococcus aureus (MRSA) is a major drug resistant bacteria that persists in both community and clinical settings due to growing resistance to current drug regimens. Thus, there is a continued need for novel compounds that are active against this organism. Previously, we reported that various rhodanine derivatives inhibited the supercoiling activity of DNA gyrase. In this study, we determined the effect of new phenylalanine-derived (Z)-5-arylmethylidene rhodanines (which are efficacious against MRSA) on the activity of the two type II bacterial topoisomerases, DNA gyrase and topoisomerase IV (Topo IV). Compounds 1 and 9 showed the greatest efficacy against DNA gyrase with a minimal inhibitory concentration (MIC) of 5 μM while compounds 2 and 3 were the most efficacious against Topo IV with MIC values of 0.75 μM and 0.5 μM, respectively. Induced fit docking, using the crystallographic structures of the target enzymes, indicated that these rhodanine derivatives bind to the ATPase domain of gyrB and ParE subunits on DNA gyrase and Topo IV, respectively. These new compounds were efficacious against both DNA gyrase and Topo IV. The increased efficacy of these new rhodanine compounds, as compared to other rhodanine derivatives, results from their dual inhibition of DNA gyrase and Topo IV, thereby making them good candidates for further drug design and development.