Antifungal resistance (AFR) has become a pressing global health threat, particularly among immunocompromised populations, leading to rising morbidity, mortality, and healthcare costs. This review explores the multifactorial drivers of AFR, including clinical overuse, agricultural fungicide application, and environmental selection pressures. Major resistant pathogens such as Candida auris and Aspergillus fumigatus exemplify the growing clinical challenge. Mechanistic insights highlight genetic mutations, efflux pump overexpression, biofilm formation, and alterations in sterol biosynthesis as key contributors to resistance. The limited antifungal pipeline, coupled with toxicity and therapeutic gaps in existing agents, further exacerbates treatment limitations. Emerging strategies—novel therapeutics like ibrexafungerp and olorofim, nanotechnology-based delivery, immunotherapies, and rapid diagnostics—show promise in combating resistance. A One Health approach, global surveillance, and robust antifungal stewardship are essential to mitigate this escalating crisis. Coordinated interdisciplinary action is critical to safeguard public health and ensure effective management of resistant fungal infections.