The incidence of methicillin-resistant Staphylococcus aureus (MRSA) having an increased rate of fluoroquinolone resistance is currently noted in Egypt necessitating the implication of new strategies to restrain the rapid spread of this resistance. The approach of repurposing could present a solution to this problem. In the current study, the efficacy of the antifungal agent, caspofungin, in increasing the susceptibility of MRSA isolated from Alexandria Main University Hospital (AMUH) to a novel fluoroquinolone, zabofloxacin, was investigated. A percentage of 30.3% of tested isolates were found to be resistant to zabofloxacin. Upon treatment with subinhibitory concentration of caspofungin, these isolates had their zabofloxacin minimum inhibitory concentration values decreased by a range varying from 2- to 32-fold. Proteomic approach was performed to provide insights into the involved mechanism of caspofungin sensitization. The profiles of cellular proteins generated by electrophoretic techniques varied between treated and untreated MRSA samples with polymorphism values ranging from 82.4 to 94.1%. Homology was detected between 1,3-beta-glucan synthase (the fungal target enzyme of caspofungin) and SdrM, a multidrug efflux pump in S. aureus. This homology was elaborated by immunoblotting analysis which showed downregulation of SdrM efflux pump proteins. The percentage of reduction in the SdrM proteins expression level varied from 18 to 61%. Caspofungin succeeded in sensitizing zabofloxacin-resistant MRSA clinical isolates by blocking the action of SdrM efflux pump and inhibiting its extrusion. Further research is urgently required to endorse the repositioning of caspofungin as an agent used in combination with zabofloxacin in the management of MRSA infections with higher efficiency.