Tissue adhesives have garnered extensive interest as alternatives and supplements to sutures, whereas major challenges still remain, including weak tissue adhesion, inadequate biocompatibility, and uncontrolled biodegradation. Here, injectable and biocompatible hydrogel adhesives are developed via catalyst-free o- phthalaldehyde/amine (hydrazide) cross-linking reaction. The hydrogels demonstrate rapid and firm adhesion to various tissues, and an o- phthalaldehyde–mediated tissue adhesion mechanism is established. The hydrogel adhesives show controlled degradation profiles of 6 to 22 weeks in vivo through the incorporation of disulfide bonds into hydrogel network. In liver and blood vessel injury, the hydrogels effectively seal the incisions and rapidly stop bleeding. In rat and rabbit models of full-thickness skin incision, the hydrogel adhesives quickly close the incisions and accelerate wound healing, which exhibit efficacies superior to those of commercially available fibrin glue and cyanoacrylate glue. Thus, the hydrogel adhesives show great potential for sutureless wound closure, hemostasis sealing, and prevention of leakage in surgical applications.