<p>Stimuli-responsive bioactive hydrogels have emerged as advanced platforms in regenerative medicine and drug delivery. Unlike static polymeric scaffolds, these “smart” systems dynamically respond to environmental cues such as pH, temperature, redox conditions, or enzymatic activity to modulate biological interactions and therapeutic outcomes. This review critically examines recent (2020–2025) advances in molecular design, functionalization, and translational development of stimuli-responsive bioactive hydrogels. Emphasis is placed on multi-stimuli responsiveness, self-healing behavior, and bioactive moiety incorporation, which together enhance tissue regeneration, drug/gene delivery, and immune modulation. The mechanistic basis of stimuli activation, cell–matrix reciprocity, and engineered bioactivity is discussed in detail. Preclinical and early clinical findings demonstrate that dynamically crosslinked hydrogels can recover up to 90% strain, silence 78% of targeted genes, and promote over 85% wound closure in animal models. Furthermore, progress in microfluidic GMP-scale manufacturing and machine learning–assisted formulation optimization is bridging the gap between laboratory innovation and clinical translation. The convergence of adaptive chemistry, artificial intelligence, and biofabrication technologies is ushering in a new era of personalized, intelligent regenerative systems. Future interdisciplinary efforts integrating mechanistic modeling, standardized biocompatibility testing, and regulatory harmonization will be crucial to advance these hydrogels from bench to bedside.</p> Graphical Abstract <p></p>