A strategy for surface hydrophobization of hydrogels via interface dynamics-induced network reconfiguration (DNR) is presented. This method enables the manipulation of hydrogel surface wettability and bioadhesion without altering the overall chemical composition or bulk properties of the hydrogels. By grafting hydrophobic yet flexible polymeric chains on mold substrates, the hydrophobic polymer backbone content in the hydrogel surface network is increased, while the presence of polar groups is reduced, transforming the hydrophilic hydrogel surface into a hydrophobic one. Experimental results show that optimal grafting density, chain length, and chain structure are critical for this transformation. Molecular dynamics simulations reveal the atomistic details of the hydrogel network reconfiguration induced by dynamic interface interactions. The hydrogels prepared using this strategy show enhanced bioadhesion and transdermal delivery compared to conventional hydrogels of the same chemical composition. The DNR strategy is versatile and applicable to various hydrogels, including double-network hydrogels and Janus hydrogels with asymmetric surface hydrophobicity. The hydrophobic surface of DNR hydrogels repels interfacial water, enhancing adhesion to wet biological tissues. The DNR hydrogels also demonstrate improved transdermal delivery of cargo molecules, as the hydrogel surface gradually becomes hydrophilic over time. The hydrogels show good biocompatibility, with no significant toxicity observed in mice. The method provides important insights into dynamic hydrogel–substrate interactions and is instrumental in the preparation of hydrogels with custom surface properties. The strategy is simple, versatile, and applicable to a wide range of hydrogel applications, including tissue adhesives, drug delivery, and hydrogel implants.A strategy for surface hydrophobization of hydrogels via interface dynamics-induced network reconfiguration (DNR) is presented. This method enables the manipulation of hydrogel surface wettability and bioadhesion without altering the overall chemical composition or bulk properties of the hydrogels. By grafting hydrophobic yet flexible polymeric chains on mold substrates, the hydrophobic polymer backbone content in the hydrogel surface network is increased, while the presence of polar groups is reduced, transforming the hydrophilic hydrogel surface into a hydrophobic one. Experimental results show that optimal grafting density, chain length, and chain structure are critical for this transformation. Molecular dynamics simulations reveal the atomistic details of the hydrogel network reconfiguration induced by dynamic interface interactions. The hydrogels prepared using this strategy show enhanced bioadhesion and transdermal delivery compared to conventional hydrogels of the same chemical composition. The DNR strategy is versatile and applicable to various hydrogels, including double-network hydrogels and Janus hydrogels with asymmetric surface hydrophobicity. The hydrophobic surface of DNR hydrogels repels interfacial water, enhancing adhesion to wet biological tissues. The DNR hydrogels also demonstrate improved transdermal delivery of cargo molecules, as the hydrogel surface gradually becomes hydrophilic over time. The hydrogels show good biocompatibility, with no significant toxicity observed in mice. The method provides important insights into dynamic hydrogel–substrate interactions and is instrumental in the preparation of hydrogels with custom surface properties. The strategy is simple, versatile, and applicable to a wide range of hydrogel applications, including tissue adhesives, drug delivery, and hydrogel implants.