Medical glue represents a suitable tool to stop wound bleeding, seal wounds, bond tissues, or implant materials. However, the development of a medical glue for durable underwater bonding remains a challenge. Herein, we developed a hydrophobic hyperbranched polymer-based medical glue with water-resistant bonding ability. Specifically, the hyperbranched polythioether (HBPTE) with abundant terminal thiol groups was first prepared through a simple one-pot thiol-Michael polyaddition reaction. Due to the hyperbranched molecular structure, HBPTE is a liquid material under room temperature, thus enabling the manufacturing of a photocurable HBPTE glue by the direct addition of poly(ethylene glycol) dimethacrylate and a photoinitiator without introduction of a solvent. This solventless HBPTE glue exhibited a maximum underwater adhesive strength of 36 kPa on porcine skin compared to only <10 kPa of the commercial fibrin glue and cyanoacrylate glue. Moreover, since the hydrophobic cross-linked network resists penetration of water, the HBPTE glue minimally swelled (2-10%) and could maintain a glass sheet structure bonded together even after 2 weeks underwater. Furthermore, an in vitro cytotoxicity test showed that the HBPTE glue did not leak any cytotoxic substances and allowed for proliferation of L929 cells on its surface. Moreover, hemocompatibility tests indicated that the HBPTE glue was nonhemolytic and did not induce thrombosis. This HBPTE glue exhibited promising characteristics to potentially find use as an underwater soft tissue adhesive or sealant.