In recent years, the integration of nanotechnology with biomedical devices has led to innovative approaches to drug delivery and therapeutic interventions. One such promising strategy involves the combination of electrospun nanofibers with microneedle arrays. This synergistic approach leverages the unique properties of both components to create a highly efficient and effective delivery system. Electrospun nanofibers possess a high surface area-to-volume ratio and adjustable attributes, making them suitable matrices for the controlled release of therapeutic agents. When combined with microneedle arrays, which offer minimally invasive and pain-free transdermal delivery, the efficacy of the system is significantly enhanced. Microneedles facilitate the penetration of nanofibers into the skin, allowing for targeted delivery of drugs directly to the desired site, thereby improving bioavailability and therapeutic outcomes. This chapter examines the underlying mechanisms that contribute to the enhanced efficacy of the combined system. It explores the fabrication techniques of electrospun nanofibers and microneedle arrays, highlighting the advantages of using biodegradable and biocompatible materials. Furthermore, it discusses the various applications of this combined system in fields such as vaccination, cancer therapy, and wound healing. The results indicate that this approach not only enhances drug permeation and retention but also reduces systemic side effects. The combination of these technologies holds promise for the development of next-generation therapeutic devices that can provide more effective and patient-friendly treatments.