Hydrogel drug delivery systems offer controlled release of therapeutic agents, including small-molecule drugs, macromolecular drugs, and cells. These systems leverage the tunable physical properties, controllable degradability, and ability to protect labile drugs from degradation. The review covers multiscale mechanisms underlying the design of hydrogel drug delivery systems, focusing on the physical and chemical properties of the hydrogel network and interactions between the hydrogel and drugs across different scales. Key mechanisms include mesh size control, network degradation, swelling, mechanical deformation, and chemical interactions such as covalent conjugation, electrostatic interactions, and hydrophobic associations. The review also discusses experimental release data, clinical translation, and quantitative comparisons between different systems to provide guidelines for rational design. Hydrogels are versatile platforms that can be tailored for specific therapeutic applications, such as cardiology, oncology, immunology, wound healing, and pain management.Hydrogel drug delivery systems offer controlled release of therapeutic agents, including small-molecule drugs, macromolecular drugs, and cells. These systems leverage the tunable physical properties, controllable degradability, and ability to protect labile drugs from degradation. The review covers multiscale mechanisms underlying the design of hydrogel drug delivery systems, focusing on the physical and chemical properties of the hydrogel network and interactions between the hydrogel and drugs across different scales. Key mechanisms include mesh size control, network degradation, swelling, mechanical deformation, and chemical interactions such as covalent conjugation, electrostatic interactions, and hydrophobic associations. The review also discusses experimental release data, clinical translation, and quantitative comparisons between different systems to provide guidelines for rational design. Hydrogels are versatile platforms that can be tailored for specific therapeutic applications, such as cardiology, oncology, immunology, wound healing, and pain management.