<p>Coumarin and indole derivatives occupy a prominent place in medicinal chemistry due to their diverse pharmacological activities, including anticancer, antimicrobial, antidiabetic, antiviral, and neuroprotective effects. Molecular hybridization, which combines two bioactive scaffolds into a single framework, has emerged as an effective strategy to improve potency, selectivity, and multifunctionality. In this context, coumarin–indole hybrids have attracted significant attention; however, no focused review has yet addressed their synthetic development. This review seeks to fill that gap by providing a critical overview of the synthetic methodologies, structure–activity relationships, and pharmacological profiles of coumarin–indole hybrids. The strategic fusion of these two privileged scaffolds has yielded compounds with notable preclinical efficacy in oncology, infectious diseases, metabolic disorders, and neurodegenerative disorders. Nevertheless, challenges such as poor bioavailability, limited target selectivity, and insufficient in vivo validation remain obstacles to clinical translation. Future progress will require structural optimization, prodrug strategies, advanced delivery systems, and systematic pharmacological and toxicological investigations. Overall, coumarin–indole hybrids represent a versatile chemotype with strong potential for the discovery of next-generation therapeutics across multiple disease domains.</p> Graphical Abstract <p></p>