Penetrating orocutaneous or oropharyngeal fistulas (POFs), severe complications following unsuccessful oral or oropharyngeal reconstruction, remain complex clinical challenges due to lack of supportive tissue, contamination with saliva and chewed food, and dynamic oral environment. Here, we present a Janus hydrogel adhesive (JHA) with asymmetric functions on opposite sides fabricated via a facile surface enzyme-initiated polymerization (SEIP) approach, which self-entraps surface water and blood within an in-situ formed hydrogel layer (RL) to effectively bridge biological tissues with a supporting hydrogel (SL), achieving superior wet-adhesion and seamless wound plugging. The tough SL hydrogel interlocked with RL dissipates energy to withstand external mechanical stimuli from continuous oral motions like chewing and swallowing, thus reducing stress-induced damage. In male New Zealand rabbit POF models, the JHA demonstrates strong adhesion and fluid-tight sealing, and maintained firm sealing for over 3 days without any decreased signs under a normal diet. After 12 days, both extraoral cutaneous and mucosal wounds achieved complete closure, with mechanical strengths comparable to normal tissues. Similar therapeutic efficacy was also confirmed in male beagle dog POF models. Thus, the proposed JHA hydrogel shows great potential for deep wound sealing and providing mechanical support to assist healing in penetrating fistulas and other injuries.