<p>Enzyme-responsive biomaterials are smart materials designed to interact with the body’s natural processes. Hydrogels, in particular, can change structure in response to specific enzymes, enabling controlled drug delivery, tissue regeneration, and improved healing. By mimicking biological environments, they provide precise, targeted treatments for conditions such as cardiovascular disease, musculoskeletal injuries, and chronic wounds. This review highlights advances in enzyme-responsive biomaterials in the recent decades, focusing on polymeric hydrogels. We examine therapeutic, scaffold, and diagnostic applications across musculoskeletal, cardiovascular, pulmonary, dental, dermal, gastrointestinal, and hepatic systems, and conclude with emerging concepts and future perspectives for clinical translation.</p>