The rise of infection caused by ‘superbugs’ is alarming and one of the most problematic resistant bacteria is methicillin-resistant Staphylococcus aureus (MRSA). This bacterium can cause a range of ailments like pneumonia, mastitis, meningitis, urinary tract infection, and post operational infection. Ten medicinal plants were investigated for their efficacy against drug-sensitive and drug-resistant strains of S. aureus. Ethanol extracts of Melianthus comosus Vahl (Melianthaceae), Melianthus major L (Melianthaceae), Dodonaea viscosa Jacq. var. angustifolia (L.f.) Benth (Sapindaceae) and Withania somnifera L. Dunal (Zygophyllaceae) were found to have good inhibitory activity against both drug-sensitive and drug-resistant strains of S. aureus. Minimum inhibitory concentrations of these plants ranged from 0.391 to 1.56 mg/ml. Ethanol extracts of all these plants were further tested for cytotoxicity on Vero cells using the XTT method. M. major exhibited a 50% inhibitory concentration (IC50) of 52.76 µg/ml and was, therefore, selected for the identification of bioactive principles. Two flavonoid compounds namely, quercetin 3-O-β-galactoside-6-gallate and kaempferol 3-O-α-arabinopyranoside, were isolated from the leaves using column chromatography. These compounds were isolated for the first time from this plant. These flavonoids did not show antibacterial activity against methicillin-sensitive strain of Staphylococcus aureus at the highest concentration (500 µg/ml) tested. The antibacterial activity of ethanol extract of M. major observed in this study could be either due to the synergistic activity of compounds present in the extract and/or due to compounds which have not been purified in this study. Good antibacterial activity of three plant extracts, namely, Melianthus comosus, Melianthus major, and Dodonaea viscose, as observed especially against MRSA, supports the use of extracts by South Africans for infections caused by S. aureus to some extent.