<p>The rapid evolution of biomaterials and biotechnology has catalyzed the development of functional drug delivery system (DDS), designed to overcome the limitations of conventional formulations, such as poor bioavailability and systemic toxicity. Amongst newly developed drug delivery system, electrospun (ES) nanofibers have emerged as a premier class of biomaterials owing to their high surface area to volume ratio, tunable porosity, and exceptional drug encapsulation efficiency. These inimitable characteristics of ES nanofibers allow for the programmable and site-specific release of therapeutic agents, making them highly versatile vehicles for localized treatment. Herein, the review discusses the contribution of ES technology and their integration into modern DDS, summarizing the strategies and modification of various ES configurations, and discussing the effects of process parameters on fibers and their application in drug delivery. Additionally, review focuses on drug release kinetics and their precise modulation by adjusting polymer, component and fabrication strategies. Thus, the applications of polymer nanofiber in diverse applications across antimicrobial therapy, cancer therapy, wound healing, treatment of cardiovascular disease and ocular delivery were summarized. By correlating the physicochemical characteristics of polymeric nanofibers with their delivery performance, this study provides a rational design framework for the next generation of advanced nanofibers, paving the way for the future frontier of personalized medicine.</p>