Adhesive hydrogels are attractive biomaterials for various applications, such as electronic skin, wound dressing, and wearable devices. However, fabricating a hydrogel with both adequate adhesiveness and excellent mechanical properties remains a challenge. Inspired by the adhesion mechanism of mussels, we used a two-step process to develop an adhesive and tough polydopamine-clay-polyacrylamide (PDA-clay-PAM) hydrogel. Dopamine was intercalated into clay nanosheets and limitedly oxidized between the layers, resulting in PDA-intercalated clay nanosheets containing free catechol groups. Acrylamide monomers were then added and in situ polymerized to form the hydrogel. Unlike previous single-use adhesive hydrogels, our hydrogel showed repeatable and durable adhesiveness. It adhered directly on human skin without causing an inflammatory response and was easily removed without causing damage. The adhesiveness of this hydrogel was attributed to the presence of enough free catechol groups in the hydrogel, which were created by controlling the oxidation process of the PDA in the confined nanolayers of clay. This mimicked the adhesion mechanism of the mussels, which maintain a high concentration of catechol groups in the confined nanospace of their byssal plaque. The hydrogel also displayed superior toughness, which resulted from nanoreinforcement by clay and PDA-induced cooperative interactions with the hydrogel networks. Moreover, the hydrogel favored cell attachment and proliferation, owning to the high cell affinity of PDA. Rat full-thickness skin defect experiments demonstrated that the hydrogel was an excellent dressing. This free-standing, adhesive, tough, and biocompatible hydrogel may be more convenient for surgical applications than adhesives that involve in situ gelation and extra agents.