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Abstract This study evaluated the possibility of using different fillers—cellulose nanocrystal, cellulose microcrystalline, wood flour, soy flour, talc, and calcium carbonate—as partial substitutes in polymeric methylene diphenyl diisocyanate (pMDI) resin. There has been concern recently regarding the use of pMDI resin due to the environmental effect of isocyanate, which is dominantly present in the resin, as well as the cost of the resin. Different fillers were used in this study as substitutes at their allowable substitution percentages. This study focused on the possibility of replacing more pMDI resin with biodegradable filler without compromising the integrity of the resin; the mechanical strength of plywood from both southern yellow pine and oak was evaluated. Fourier-transform infrared spectroscopy, scanning electron microscopy, and thermogravimetric analysis were conducted to study the effect of modification on the bond-line quality of the final product. The effects of different fillers on adhesion properties of the pMDI resin were tested on the plywood according to the American Society for Testing and Materials (ASTM D–906-64) standard. The results showed that shear strength of the modified pMDI resins ranged from 0.3 to 1.083 MPa and 0.35 to 1.178 MPa for oak and pine plywoods, respectively. The modified samples with soy flour showed significant improvement in the shear strength with 261 and 236 percent higher shear strength than the control (pMDI) for samples from hardwood and softwood, respectively. Partial substitution of pMDI resin with soy flour at 30 percent substitution substantially improves the adhesion properties of pMDI resin.