ABSTRACT Wet‐tissue adhesives face challenges in achieving tough wet adhesion because the hydration layer on the tissue surface hinders the formation of interfacial bonds. Inspired by the cation‐mediated wet adhesion in barnacles, a strong wet tissue adhesive hydrogel, P(mPEI‐AA‐AMH 1 ), is prepared by photo‐initiated copolymerization of acrylic acid (AA), cationic monomer (AMH) and modified polyethyleneimine (mPEI). mPEI is a kind of polyelectrolyte containing various amino cations and carbon–carbon double bonds, which helps to enhance the wet adhesion and mechanical properties of the hydrogel. Its adhesion strength on moist porcine skin is ~115 kPa, while the interfacial toughness on moist porcine skin is ~422 J/m 2 , which can effectively close rat femoral artery wound. Additionally, the hydrogel exhibits good antibacterial properties and biosafety. The antibacterial efficacy of the P(mPEI‐AA‐AMH 1 ) hydrogel against E. coli reaches an impressive 99.23% ± 0.24%, and against Staphylococcus aureus reaches 99.1% ± 0.45%. The P(mPEI‐AA‐AMH 1 ) hydrogel has good tissue‐selective adhesion due to its hydrogen bonding and electrostatic interactions with the negatively charged tissue surface. It shows minimal adhesion to medical devices and is easy to apply, which is expected to provide theoretical support for the future development of wet adhesive hydrogels in medical applications.