Non-healing corneal ulcers, also referred to as refractory or persistent epithelial defects, represent a significant challenge in ophthalmic practice due to their complex etiology and resistance to conventional therapies. These ulcers arise from a multitude of infectious and non-infectious factors, including microbial infections, autoimmune diseases, neurotrophic keratitis, and iatrogenic causes, leading to prolonged inflammation, stromal degradation, and impaired epithelial regeneration. This review provides a comprehensive overview of the anatomy and physiology of the cornea, elucidating the pathophysiological mechanisms underlying non-healing ulcers. It further explores the diagnostic modalities employed to identify these ulcers and differentiates them from other corneal pathologies. Current treatment strategies, encompassing medical management, surgical interventions, and barrier therapies, are critically analyzed. Special emphasis is placed on emerging therapeutic innovations such as stem cell therapy, tissue engineering, gene therapy, nanotechnology-based drug delivery systems, and artificial corneas, which offer promising avenues for effective management of refractory cases. The review also highlights the persistent challenges in treating these ulcers, including antibiotic resistance, delayed diagnosis, and management of chronic or recurrent cases. Finally, it outlines future directions and recommendations for improving patient outcomes through multidisciplinary care, biomarker development, and continued clinical research in this evolving field. © 2025 Elsevier B.V., All rights reserved.