This study evaluates the effect of 1% to 5% NaOH treatments of cotton stalk particles on the chemical composition and physical and mechanical properties of particleboards produced with this material. Gas chromatography and Fourier transform infrared (FTIR) spectroscopy indicated that the extractive, hemicellulose, and lignin content of the particles decreased during the alkali treatments, whereas the cellulose content increased. Thermogravimetric analysis (TGA) indicated that the untreated particles exhibited higher thermal stability than the particles treated with NaOH. The decrease in thermal stability of alkali-treated particles seems to be due to degradation of chemical components. Alkali treatments raised water absorption (WA) and thickness swelling (TS) of the produced particleboards. Except for 1% NaOH, the treatments reduced the modulus of elasticity (MOE), modulus of rupture (MOR), and internal bond (IB) strength in relation to the board made with untreated particles. The 1% NaOH treatment of cotton stalks was more effective and beneficial, leading to particleboards with satisfying MOE, MOR, and IB values that met the requirements for general-purpose particleboards used in dry conditions, as indicated by the TS-EN 312 (2012) standard.