HDI-BPA phenolic resin is synthetised by bisphenol A formaldehyde phenolic resin (BPA phenolic resin) and hexamethylene diisocy-anate (HDI) under the catalysis of dibutyltin dilaurate (DBTDL). The chemical structure and molecular weight of HDI-BPA phenolic resin are characterize by FTIR, 1H NMR, GPC and organic element analysis. The results show that HDI-BPA phenolic resin is suc-cessfully prepared and its Mw is 3376. In addition, the effects of reaction temperature, reaction time, material ratio and amount of cata-lyst on the content of isocyanate and grafting ratio in the target product are discussed. The synthesis process of HDI-BPA phenolic resin is optimize by Box-Behnken Design (BBD) in response surface methodology by establishing a quadratic regression equation of isocyanate content and grafting ratio. The optimum conditions are as follows: a reaction temperature of 32 °C, a reaction time of 55 min, a ratio of m (BPA phenolic resin), m (HDI) and m (DBTDL) of 1∶4.759∶0.012. Under this condition, the content (mass fraction) of the isocyanate group in the final product is 25.51 %, and its graft ratio is 48.929 %. Finally, a HDI-BPA phenolic resin adhesive is prepare by adding a curing agent to the HDI-BPA phenolic resin. Its maximum adhesion is 283.69 N, which is 3.7 times higher than that of BPA phenolic resin adhesives, indicating that HDI modification can significantly improve the adhesion of BPA phenolic resin to low polarity leather substrates. At the same time, the contact angle of HDI-BPA phenolic resin adhesive is 93.5°, which shows good hydrophobic properties and water resistance.