<p>The widespread issue of counterfeit pharmaceutical drugs presents a significant global challenge, especially for regions that are resource-constrained and have weak regulations and fragmented verification systems. Conventional methods, such as bar codes, holograms, and centralized databases have inherent weaknesses with regard to limited traceability, susceptibility to tampering, and an absence of trust by end-users. This paper proposes a comprehensive blockchain-based drug verification framework that incorporates smart contracts, role-based access, and a hybrid on/off-chain architecture, all of which may be used to verify a drug’s chain of custody, in real-time and in a tampered-proof way. The framework consists of a permissioned blockchain for secure logging, smart contract validation logic to provide autonomous validation logic, and Internet of Things (IoT). In order to provide the theoretical foundation for the latency of verification, authenticity accuracy, and validation probability, a mathematical model has been proposed. The framework testbed has been implemented using Hyperledger Fabric in a simulated drug supply chain that includes manufacturers, distributors, and pharmacies. Validation of over 10,000 synthetic transactions has been achieved at the cryptographic level. The performance of the proposed model was evaluated in comparison to four, state-of-the-art blockchain verification models using four distinct metrics such as, latency, throughput, false detections, and computational complexity. Generally speaking, the results indicate that the proposed framework reached lower latency at nearly 45%, reached higher throughput at nearly 30%, and reached nearly perfect accuracy (AUROC = 0.991), which validates the feasibility of the proposed framework to provide real-time, scalable drug verification, authentication, and transparency in a complex supply chain.</p>