Hydrogels have emerged as one of the most versatile biomaterial platforms for advanced drug delivery, offering tunable physicochemical properties, high water content, and structural similarity to biological tissues. This review synthesizes evidence from 432 high-quality studies to evaluate the evolution, performance, and translational potential of hydrogel-based drug delivery systems. Early hydrogels functioned primarily as passive, diffusion-controlled carriers, but advances in polymer chemistry, supramolecular assembly, nanotechnology, and biofabrication have led to the development of responsive, multifunctional systems capable of precise spatiotemporal control over therapeutic release. Findings demonstrate significant progress in stimuli-responsive hydrogels, injectable and shear-thinning networks, nanocomposite architectures, and 3D-printable bioinks, all of which enable improved mechanical stability, enhanced drug loading, and compatibility with small molecules, peptides, proteins, and nucleic acids. Despite these advancements, challenges persist in predicting in vivo release behavior, ensuring long-term biocompatibility, and overcoming regulatory barriers, including the lack of standardized protocols for evaluating long-term in vivo stability, degradation products, and toxicity—particularly for multifunctional and nanocomposite hydrogels. Emerging directions—such as AI-driven materials design—highlight the potential for next-generation intelligent delivery systems. In this context, machine learning models are increasingly used to predict polymer-drug interactions, drug loading efficiency, and release kinetics based on molecular descriptors and network architecture. Data-driven approaches can also optimize cross-linking chemistry, crosslink density, and mechanical properties, enabling rapid in silico screening of hydrogel formulations and significantly reducing experimental trial-and-error during development. Overall, hydrogels continue to advance as adaptable and clinically relevant platforms, but their translation into approved therapies will require standardized characterization methods, scalable fabrication routes, and deeper understanding of biological interactions. This review provides a comprehensive foundation for guiding future innovations and accelerating clinical adoption of hydrogel-based drug delivery technologies.
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