Hydrogels are promising drug delivery systems that can control the release of various therapeutic agents, including small-molecule drugs, macromolecules, and cells. They offer spatial and temporal control over drug release, and their tunable physical properties, controllable degradability, and ability to protect labile drugs make them suitable for drug delivery. This review discusses the multiscale mechanisms underlying hydrogel drug delivery systems, focusing on the physical and chemical properties of the hydrogel network and the interactions between the hydrogel and the drug across different scales. It also reviews experimental release data, clinical translation, and quantitative comparisons between different systems to guide the rational design of hydrogel delivery systems. Conventional drug administration often requires high dosages or repeated administration, which can reduce efficacy and patient compliance. Controlled drug delivery systems, including hydrogels, have been developed to address these issues. Hydrogels can be delivered in various ways, such as surgical implantation, local injection, or systemic delivery. The choice of delivery method depends on maximizing efficacy and patient compliance. The release of drugs from hydrogels is crucial for achieving therapeutic outcomes, and the duration and profile of drug release depend on the specific application. Hydrogels can be classified into macroscopic, microgels, and nanogels based on their size. Macroscopic hydrogels are typically used for implantation or transdermal delivery, while microgels and nanogels are used for minimally invasive delivery. The size and properties of hydrogels affect their ability to adhere to biological barriers and their biodistribution. Bioadhesive properties are important for drug delivery, as they allow hydrogels to remain at the target site for longer periods. The mesh size of hydrogels controls drug diffusion and release. Larger mesh sizes allow for faster diffusion, while smaller mesh sizes can slow down drug release. The mesh size can be controlled by adjusting the polymer and cross-linker concentrations. The degradation of hydrogels can also be used to control drug release, with hydrolysis or enzyme activity mediating the degradation process. Swelling of hydrogels can also be used to control drug release, with the extent of swelling depending on external conditions such as pH, temperature, and ionic strength. Mechanical deformation of hydrogels can also be used to control drug release, with the deformation triggering convective flow within the network. The release of drugs from hydrogels can be controlled through various interactions, including covalent conjugation, electrostatic interactions, and hydrophobic associations. These interactions can be used to design hydrogels that provide controlled and sustained drug release. The design of hydrogels across different length scales allows for the optimization of drug delivery systems, with the combination of different mechanisms enabling fine control over drug presentation.Hydrogels are promising drug delivery systems that can control the release of various therapeutic agents, including small-molecule drugs, macromolecules, and cells. They offer spatial and temporal control over drug release, and their tunable physical properties, controllable degradability, and ability to protect labile drugs make them suitable for drug delivery. This review discusses the multiscale mechanisms underlying hydrogel drug delivery systems, focusing on the physical and chemical properties of the hydrogel network and the interactions between the hydrogel and the drug across different scales. It also reviews experimental release data, clinical translation, and quantitative comparisons between different systems to guide the rational design of hydrogel delivery systems. Conventional drug administration often requires high dosages or repeated administration, which can reduce efficacy and patient compliance. Controlled drug delivery systems, including hydrogels, have been developed to address these issues. Hydrogels can be delivered in various ways, such as surgical implantation, local injection, or systemic delivery. The choice of delivery method depends on maximizing efficacy and patient compliance. The release of drugs from hydrogels is crucial for achieving therapeutic outcomes, and the duration and profile of drug release depend on the specific application. Hydrogels can be classified into macroscopic, microgels, and nanogels based on their size. Macroscopic hydrogels are typically used for implantation or transdermal delivery, while microgels and nanogels are used for minimally invasive delivery. The size and properties of hydrogels affect their ability to adhere to biological barriers and their biodistribution. Bioadhesive properties are important for drug delivery, as they allow hydrogels to remain at the target site for longer periods. The mesh size of hydrogels controls drug diffusion and release. Larger mesh sizes allow for faster diffusion, while smaller mesh sizes can slow down drug release. The mesh size can be controlled by adjusting the polymer and cross-linker concentrations. The degradation of hydrogels can also be used to control drug release, with hydrolysis or enzyme activity mediating the degradation process. Swelling of hydrogels can also be used to control drug release, with the extent of swelling depending on external conditions such as pH, temperature, and ionic strength. Mechanical deformation of hydrogels can also be used to control drug release, with the deformation triggering convective flow within the network. The release of drugs from hydrogels can be controlled through various interactions, including covalent conjugation, electrostatic interactions, and hydrophobic associations. These interactions can be used to design hydrogels that provide controlled and sustained drug release. The design of hydrogels across different length scales allows for the optimization of drug delivery systems, with the combination of different mechanisms enabling fine control over drug presentation.