Corn distiller’s dried grains with solubles (DDGS) is mostly marketed as a livestock feed due to its high protein content of 30%. Recently, the proteins in DDGS have shown potential to act as binding agents along with melamine-urea-formaldehyde resin. However, it is unknown if DDGS can be chemically functionalized as a natural binder to replace synthetic resin in particleboard. In this study, several formulations were tested using various concentrations of acetic acid and sodium hydroxide treatments with combinations of temperature, DDGS concentrations, particle sizes, and wax. FTIR results indicated that DDGS proteins were decoupled through acid or alkali treatments, and acid treated DDGS in particleboards displayed higher improvements in internal bond strength as well as the moisture resistance of the particleboards. These results suggest that acid or alkali treated DDGS has potential to act as a natural binder for manufacturing medium-density particleboard.