Adhesiveness, as one of the basic properties of hydrogels, has attracted much attention in the fields of medical bandage, flexible wearable device, and electrolyte. However, the adhesive property is difficult to be adjusted on the surfaces of different substrates. Herein, casein, a model of protein, and a hydrophobic monomer (2-methoxyethyl acrylate, MEA) are successfully introduced into polyacrylamide (pAAm) hydrogels. As a result, the pAAm–MEA–Casein hydrogels exhibited not only good mechanical property based on the multiple physical crosslinking, but also excellent adhesive adjustability for different hydrophobic and hydrophilic surfaces through the regulation of hydrophobic interactions. The tensile stress of pAAm–MEA–Casein hydrogels can achieve 258 kPa with a strain of around 2200%. The adhesive performance is always kept after 40 times repeatedly bonding to the silicon rubber surface, and the interfacial toughness is around 115.22 J m. Moreover, the adjustable bonding of the hydrogel to the hydrophilic and hydrophobic materials can be achieved by changing the content of hydrophobic segments. This protein-driven hydrophobic association strategy would open a new approach to design a new generation of adjustable adhesion soft materials for biomedical engineering.