Acorus calamus is widely used as an Indian medicinal plant and extensively reported for treatments of skin, digestive and nervous disorders. A methanol extract of A. calamus (rhizome) showed maximum extraction yield of 4% (w/w) followed by 3% (w/w) in water. Total 8 Staphylococcus aureus isolates were obtained from nose, groin, wounds, axilla, throat of various patients exhibited strong β-lactamase activity and antibiotic resistance for ampicillin, oxacillin, and methicillin coded for mec A gene. Thus, all isolates belong to methicillin-resistant Staphylococcus aureus (MRSA) class. Methanol extract is the most potent MRSA antibacterial extract followed by water, n-butanol and chloroform. Minimum inhibitory concentration (MIC) of methanol extract varied from 1.25 to 2.50 mg/ml for all MRSA isolates which also exhibited highest MIC values of 512 µg/ml and 128 µg/ml for ampicillin and oxacillin antibiotics, respectively. Interestingly, the synergistic interaction of 128 µg/ml of A. calamus methanol extract with antibiotics (ampicillin, 64 µg/ml and oxacillin, 32 µg/ml) showed lowered MICs. All extracts of A. calamus and β-asarone showed no significant cytotoxic activity against non-cancerous 3T3 fibroblasts cells which was confirmed by MTT assay on MRSA-08 isolate. Antibacterial effect and preventive invasion properties of MRSA of methanol extract of A. calamus were found to be potent when compared with β-asarone, an active component of A. calamus. The present investigation showed a correlation of polyphenolics and flavonoid based major phytochemical constituents with bioactivities on MRSA revealed A. calamus as a potential non-toxic drug candidate for various skin diseases.