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<i>Staphylococcus aureus</i> is one of the ESKAPE (<i>Enterococcus faecium</i>, <i>Staphylococcus aureus</i>, <i>Klebsiella pneumoniae</i>, <i>Acinetobacter baumannii</i>, <i>Pseudomonas aeruginosa</i>, and <i>Enterobacter</i> species) pathogens among which multidrug resistance has emerged. Resistance to methicillin has resulted in clinicians using the antibiotic of last resort, vancomycin, to treat infections caused by methicillin-resistant <i>S. aureus</i> (MRSA). However, excessive use and misuse of vancomycin are major causes of resistance among <i>S. aureus</i> strains. South Asia encompasses ~25% of the world’s population, and countries in South Asia are often characterized as low- and middle-income with poor healthcare infrastructure that may contribute to the emergence of antibiotic resistance. Here, we briefly highlight the mechanism of vancomycin resistance, its emergence in <i>S. aureus</i>, and the molecular epidemiology of non-susceptible <i>S. aureus</i> to vancomycin in the South Asian region.