OBJECTIVE: To search systematically for an alternative therapy with compounds particularly from plant origin. METHODS: Efficacy test of different root extracts of Withania somnifera (W. somnifera) (L) Dunal against multi drug resistant (MDR) Staphylococcus aureus (S. aureus) variants was performed following the agar well diffusion method. Evaluation of susceptibility pattern of the isolates was carried out by employing disk diffusion method using standard antibiotic disks. RESULTS: In vitro study with W. somnifera root extracts was found to be effective against all the MDR S. aureus strains isolated from local and patient sources. Different root extracts of WS showed different degree of effectiveness against the isolates. CONCLUSIONS: The major active principles responsible for the antibacterial efficacy were mainly present in methanol (MeOH)extract and ethanol (EtOH) extracts as well as in butanol (BuOH) extract fraction. Amongst all the extracts the BuOH fraction was found to be most active against all the isolates but aqueous extract was the least active one. Finally it may be concluded that the antimicrobials from W. somnifera may raise an alternative therapy for MDR staphylococcal infections in near future.