Hydrogels have emerged as versatile therapeutic platforms with immense potential for treating various diseases, due to their tunable properties and biocompatibility. Recent innovations, including injectable, self-assembling, and bioadhesive hydrogels, have broadened their biomedical applications, driven by advancements in materials chemistry. This review systematically examines the role of chemical principles in designing and customizing therapeutic hydrogels, with a focus on hydrogelation mechanisms, swelling ratios, mechanical properties, and biological interactions. By highlighting key studies in this field, this review explores how chemical chain modifications, cross-linking strategies, and cargo delivery systems have been tailored to achieve diverse functions, such as drug depots, wound dressings, antiadhesive barriers, and regenerative scaffolds. Addressing the gap in comprehensive analyses, this review underscores the integration of chemical design principles to optimize hydrogel properties for targeted therapies and discusses future opportunities to advance therapeutic hydrogel technology for a wide range of biomedical applications.