<p>In recent years, microbial infections have become the most common and the leading cause of death worldwide. From them, the Gram-positive bacterial strain <i>Staphylococcus aureus</i> is a highly effective pathogen that can infect almost every human body tissue, from minor skin diseases to life-threatening infections. Antibiotics are generally used to treat microbial infections, but due to their excessive and careless usage, microorganisms have gradually developed resistance to them. Therefore, it is necessary to develop novel drugs that minimize drug resistance. Many microbial drugs are available in the market but they are not as effective as before. Currently, coumarin derivatives are highly regarded in medicinal chemistry and favored by new researchers due to their diverse pharmaceutical properties, including antibacterial, anticancer, antitubercular, antioxidant, etc. It also possesses antibiotic qualities as well. Coumarines are commercially available and have long been utilized in clinical treatment. These therapeutic properties of coumarin can help to develop novel antimicrobial agents to treat drug resistance. Hence, this review article provides significant attention to the recent developments and structure–activity relationships (SAR) of C-3 substituted coumarin derivatives to combat infection caused by <i>S. aureus</i>.</p> Graphical abstract <p></p>