Drug-loaded microspheres are an innovative technology in drug delivery systems (DDS), addressing many limitations of conventional methods. Their ability to enable controlled release, precise targeting, and broad drug compatibility makes them a versatile platform with significant potential in modern medicine. This review explores the unique properties of microspheres, including their biocompatibility, biodegradability, and customizable architecture, positioning them as promising candidates for therapeutic use in cancer, diabetes, and rheumatoid arthritis. These characteristics enhance drug stability and bioavailability while reducing systemic side effects, improving patient outcomes. The key findings discussed in this review highlight critical factors influencing microsphere performance, including material selection, particle size, surface modification, and multi-drug loading strategies. Particularly, the integration of nanoscale materials and the combination of microsphere technology with gene therapy and immunotherapy have shown great potential to improve treatment precision and efficacy. However, challenges such as large-scale production, reproducibility, and optimization of drug release profiles remain significant hurdles. Large-scale manufacturing of microspheres with consistent size, efficient drug loading, and predictable release patterns is technically complex, and optimizing release, especially for drugs with narrow therapeutic windows, requires a deeper understanding of the interactions between drugs and polymers. Future advances in microsphere technology are expected to leverage innovations in nanotechnology, gene therapy, and immunotherapy. These advancements may enable more efficient and personalized treatments for diseases that were previously difficult to treat. The findings presented in this review emphasize the transformative potential of microspheres in revolutionizing drug delivery, offering safer, more effective, and patient-specific therapies.