Plumbagin (5‐hydroxy‐2‐methyl‐1,4‐napthoquinone) is a bicyclic naphthoquinone, found in three major plant families viz. Plumbaginaceae, Ebenceae and Droseraceae. The phytochemical is reported to exhibit various pharmacological properties. In this study, plumbagin isolated from Plumbago zeylanica L. was investigated for its in vitro activity against methicillin‐resistant Staphylococcus aureus (MRSA). Against 100 MRSA isolates that included multi‐drug‐resistant phenotypes, plumbagin showed consistent activity with a narrow minimum inhibitory concentration (MIC) range of 4–8 μg ml−1. The time‐kill study revealed 99% kill of a reference MRSA strain, 8 h after exposure to plumbagin. In the combination MIC study using the reference MRSA strain, plumbagin showed synergistic effect with ciprofloxacin and piperacillin while additive or indifference effect with other commonly used antibiotics. The transmission electron micrograph of the reference MRSA strain treated with plumbagin confirmed cell wall and cytoplasmic changes. Our results demonstrated potent anti‐MRSA activity of plumbagin which was not impacted by multi‐drug resistance. This is a first ever study that evaluated in vitro anti‐MRSA activity of plumbagin employing large number of MRSA isolates. The findings of this study support the need for the further investigation on this phytochemical agent for therapeutic application. Significance and Impact of the Study This study revealed phytochemical plumbagin's potent and consistent in vitro antibacterial activity against clinically problematic methicillin‐resistant Staphylococcus aureus (MRSA) including multi‐drug‐resistant (MDR) phenotypes. The study results support further research to assess the clinical scope of plumbagin.