Underwater adhesives have great potential applications in biomedical fields. However, it is challenging to realize underwater adhesion due to screening by highly hydrated layer at the interface. To tackle this problem, here we present a novel strategy that combines hydrophobic association and supramolecular interactions to achieve robust adhesion at wet interfaces. Hydrophobic monomers (hexyl acrylate and styrene) are copolymerized with hydrophilic acrylic acid (AAc), and bifunctional host/guest assembly of β-cyclodextrin and adamantane to produce an adhesive. Herein, hydrophobic segments segregate to form hydrophobic microdomains both inside and at the interface. Internal hydrophobic clusters and host–guest interactions serve as physical crosslinks to improve the mechanical properties. Meanwhile, hydrophobic domains at surface play a critical role in expelling water and building a hydrophobic environment to minimize interference from water, where the hydrophilic units form hydrogen bonding, electrostatic attraction, coordination, and cation-π interactions to adhere on the surface. Lap shear tests indicate adhesion strength of about 92 ∼ 116 kPa on glass, copper, plastic, wood, and bone. Such a strong adhesion is independent of environment changes, including pH, PBS and NaCl solutions. More importantly, the adhesive shows excellent adhesion performance for bone, with adhesion strength up to 112.58 kPa in air and 91.51 kPa underwater. The strategy to combine hydrophobic interactions and supramolecular interactions may open a new avenue to the development of new adhesives for underwater adhesion and biological tissue.