The aim of this study was to improve the water resistance of a soy protein-based bio-adhesive using a melamine/epichlorohydrin prepolymer (MEP). The multi-epoxy groups in the MEP reacted with active groups on the protein molecule and formed a crosslinked and denser network, which improved the water resistance of the resulting adhesive. In addition, the addition of a MEP increased the thermal ability of the cured adhesive and created a smooth surface with fewer holes and cracks preventing moisture intrusion and further improving the water resistance of the resulting adhesive. Furthermore, the use of MEP introduced a rigid structure into the adhesive formulation, which increased the rigidity of the cured adhesive, and further increased the water resistance of the adhesive. Incorporating 6 wt% MEP effectively improved the water resistance of the adhesive by 10.5%. The wet shear strength of the plywood bonded with the resultant adhesive increased by 281.1% to a maximum value of 1.41 MPa, which was higher than that of the soy beanmeal/PAE adhesive and commercial MUF and UF resin. This improvement in the resultant plywood was attributed to the adhesive water resistance improvement and additional interlock formation between the wood and adhesive resulting from the higher solid content of the adhesive as well as the viscosity reduction. The resultant adhesive has a solid content of 32.65% and viscosity of 499, 400 mPa s, which is acceptable for the industrial application of plywood fabrication.