Metal-free click chemistry has emerged as a powerful tool for fabricating hydrogels with controlled physicochemical properties for biomedical applications. This review highlights recent advances in using metal-free click reactions to synthesize hydrogels and their applications. Hydrogels are three-dimensional polymeric networks that can retain large amounts of water and are used in biosensing, drug delivery, and tissue engineering. Traditional methods for hydrogel fabrication involve chemical cross-linking, but metal-free click reactions offer advantages such as high efficiency, biocompatibility, and the ability to fabricate injectable and microstructured gels. Key metal-free click reactions include the Diels-Alder (DA) and inverse electron demand Diels-Alder (IEDDA) cycloadditions, thiol-ene radical addition, Michael-type thiol-ene reactions, strain-promoted azide-alkyne cycloaddition (SPAAC), Schiff-base reaction, thiol-epoxy, and amine-epoxy reactions. These reactions enable the formation of well-defined hydrogels with tunable mechanical and degradation properties. For example, DA-based hydrogels can be self-healing and redox-responsive, while IEDDA-based hydrogels are fast, selective, and biocompatible. Thiol-ene reactions are efficient and can be used to fabricate injectable hydrogels for cell encapsulation and drug delivery. SPAAC reactions are particularly useful for biocompatible hydrogels, as they do not require metal catalysts and produce minimal byproducts. These hydrogels have been applied in tissue engineering, drug delivery, and biomedical imaging. For instance, hydrogels based on hyaluronic acid and PEG have been used for bone repair and cancer treatment. Thiol-maleimide reactions have been used to fabricate hydrogels with controlled drug release and cell encapsulation. The use of metal-free click reactions is increasingly preferred due to their biocompatibility and ability to avoid toxic metal impurities. Overall, metal-free click chemistry offers a versatile and efficient approach for fabricating hydrogels with tailored properties for biomedical applications.Metal-free click chemistry has emerged as a powerful tool for fabricating hydrogels with controlled physicochemical properties for biomedical applications. This review highlights recent advances in using metal-free click reactions to synthesize hydrogels and their applications. Hydrogels are three-dimensional polymeric networks that can retain large amounts of water and are used in biosensing, drug delivery, and tissue engineering. Traditional methods for hydrogel fabrication involve chemical cross-linking, but metal-free click reactions offer advantages such as high efficiency, biocompatibility, and the ability to fabricate injectable and microstructured gels. Key metal-free click reactions include the Diels-Alder (DA) and inverse electron demand Diels-Alder (IEDDA) cycloadditions, thiol-ene radical addition, Michael-type thiol-ene reactions, strain-promoted azide-alkyne cycloaddition (SPAAC), Schiff-base reaction, thiol-epoxy, and amine-epoxy reactions. These reactions enable the formation of well-defined hydrogels with tunable mechanical and degradation properties. For example, DA-based hydrogels can be self-healing and redox-responsive, while IEDDA-based hydrogels are fast, selective, and biocompatible. Thiol-ene reactions are efficient and can be used to fabricate injectable hydrogels for cell encapsulation and drug delivery. SPAAC reactions are particularly useful for biocompatible hydrogels, as they do not require metal catalysts and produce minimal byproducts. These hydrogels have been applied in tissue engineering, drug delivery, and biomedical imaging. For instance, hydrogels based on hyaluronic acid and PEG have been used for bone repair and cancer treatment. Thiol-maleimide reactions have been used to fabricate hydrogels with controlled drug release and cell encapsulation. The use of metal-free click reactions is increasingly preferred due to their biocompatibility and ability to avoid toxic metal impurities. Overall, metal-free click chemistry offers a versatile and efficient approach for fabricating hydrogels with tailored properties for biomedical applications.