Aim Emergence of extended‐spectrum beta‐lactamase (ESBL) producing with quinolone‐resistant (QR) pathogenic Enterobacteriaceae augmented the need to establish therapeutic options against them. Present study aimed towards determination of synergistic combination of eugenol (EG) with cefotaxime (CTX) and ciprofloxacin (CIP) to combat against this resistance and potentiation of antibacterial drugs by EG against these bacteria. Methods and Results Synergistic interaction between EG and CTX/CIP (FICI: 0·08–0·5) were observed among ESBL‐QR bacteria using checkerboard assay. Approximately, 2‐ to 1024‐fold minimum inhibitory concentration value reduction and 17‐ to 165 030‐fold dose reduction index strongly suggested synergistic interaction between EG and antibiotics. Cell viability assay showed reduction in log10 CFU per ml from 16·6 to 3·1 at synergistic concentration. Scanning electron microscopy further proved disruptive effect of EG on cell architecture. Eugenol and/or its combination also altered genes’ expressions that imparted antibiotic resistance by ~1·6 to ~1226 folds. Conclusions Reduced doses of antibiotics, bacterial morphological alterations, efflux pump down regulation, porin over expression and beta‐lactamase gene inhibition of ESBL‐QR bacteria by EG alone or in combination with CTX/CIP might have reversed antibiotic resistance profile of ESBL‐QR bacteria. Significance and Impact of the Study This study provided a molecular insight into action of EG and/with CTX and CIP, which might have potentiated antibiotic’s activity against ESBL‐QR bacteria.