AbstractAntimicrobial resistance is a major threat to mankind. Many frontline medications are ineffective against antimicrobial‐resistant strains which are also responsible for the high mortality rate worldwide. The urgency to create new sets of antimicrobial agents is a priority in present circumstances. In continuation to this, we have strategically designed and synthesized some novel hybrids of 4‐thiazolidinone bearing coumarin and pyridine cores for the evaluation of antimicrobial efficacy. A three‐step multicomponent reaction was performed via imine formation, cyclization, and Knoevenagel condensation for the synthesis of titled compounds (5a‐o). The synthesized entities were characterized through different analytical techniques, that is, IR, 1H NMR, 13C NMR, and mass spectra. On evaluating the potency of our synthesized hybrids, we received some promising results. Compound 5m was identified as the most potent component possessing 50 μg/ml (minimum inhibitory concentration [MIC] value) against S. aureus and 250 μg/ml (MIC value) against C. albicans strains. Further, a molecular docking study against microbial DNA gyrase was carried out to understand the binding profile of synthesized molecules, which supported their in‐vitro antimicrobial activity. These data helped to gain an insight into their plausible mechanism of action. Their binding affinity scores correlated well with the in‐vitro antimicrobial activities while their binding modes proposed the involvement of steric, electrostatic, and hydrogen‐bonding interactions with the active site.