This study addresses the drug shortage crisis, which disproportionately affects rural U.S. hospitals, where supply chain vulnerabilities threaten patient safety and institutional viability as pharmaceutical shortages increased from 61 cases in 2005 to 178 annually by 2010. The research develops comprehensive supply chain optimization strategies specifically designed for rural healthcare facilities to enhance medication accessibility, improve supply chain resilience and ensure reliable pharmaceutical distribution across geographically isolated communities. The study employs a systematic literature review of 46 pharmaceutical supply chain studies. The findings reveal that rural hospitals experience medication price increases of 300-500% during shortages, which creates unsafe conditions of 60% however, forcing costly treatment modifications and patient transfers that strain already limited resources. The research demonstrates that artificial intelligence-driven demand forecasting, automated inventory management systems, blockchain-enabled transparency and the USDA Rural Development Program's which integrates infrastructure investments, offer transformative potential for supply chain optimization. The study concludes that successful pharmaceutical supply chain resilience requires coordinated implementation of predictive analytics, value-based procurement strategies and collaborative resource sharing mechanisms that address systemic distribution network weaknesses, however, ensuring equitable medication access across rural America's healthcare safety net.