<p>In light of the propagation of resistance amongst bacteria, many infections are currently difficult to treat, with extremely high death and morbidity rates. Thus, we investigated the effect of using a combination of amoxicillin and broccoli ethanolic extract against <i>Staphylococcus aureus</i> infections. Broccoli or <i>Brassica oleracea</i> active metabolites’ were to be identified and quantified using high-performance liquid chromatography (HPLC). The major detected compounds were chlorogenic acid and gallic acid. In vitro, the combination of amoxicillin with broccoli revealed fractional inhibitory concentration index of the amoxicillin-broccoli combination was less than 0.5 in 50% of the isolates, which indicates a synergetic potential. The in vivo study revealed a notable lessening in the bacterial count present in the examined tissues in the employed systemic infection model. The studied tissues were kidney, liver, and spleen. Moreover, the histological characteristics were found to have a remarkable enhancement in the combination-treated group. Thus, future clinical reports have to be employed to explicate the usefulness of such a combination in the clinical practice.</p> Graphical abstract <p></p>