A water‐resistant adhesive for plywood panels for engineered wood floors was developed using thermal–chemically treated wheat flour (WF), polyvinyl alcohol (PVA), and polymeric diphenylmethane diisocyanate (p‐MDI) as the cross‐linker. The thermal–chemical treatment was performed at 100°C in the presence of sulfuric acid or sodium dodecyl sulfate (SDS). Fourier transform infrared spectroscopy, X‐ray diffraction spectroscopy, and scanning electron microscopy were used to investigate the chemical structure, crystalline degree, and morphology change, respectively, of the thermal–chemically treated WF. The boiling water‐insoluble content and acetaldehyde values of the thermal–chemically treated WF were also evaluated and compared with those of the controls—native WF and thermally treated WF alone. The bond property evaluation showed that the water resistance of the thermal‐SDS‐treated WF (T‐SDS‐WF)‐based adhesive was significantly improved, which is mainly attributed to the formation of a three‐dimensional crosslinking network resulting from self‐crosslinking of the wheat protein, the Maillard reaction between the wheat starch and wheat protein, and the increased crosslinking between T‐SDS‐WF and p‐MDI. Overall, the developed WF‐based adhesive is a promising bio‐based candidate in the production of plywood for engineered wood floors.