Physical properties are one of the drawbacks of oil palm wood (OPW) and they need to be improved via an appropriate method. The response surface methodology (RSM) based on central composite design (CCD) was used to evaluate and optimize the parameters of a hydrothermal treatment and to create an empirical model of the mass loss (ML, %), equilibrium moisture content (EMC, %), and anti-swelling efficiency (ASE24h, %) responses. This study focused on the effect of hydrothermal treatment (HTT) in buffer solutions to control the destructive effects of released acids caused by the degradation of hemicellulose acetyl groups. A CCD, as the most common RSM design, was applied with three treatment factors including the buffer solutions (acidic, neutral, and alkaline with pH of 5 to 8), temperature (80 to 140 °С), time (40 to 120 min), and a total of 20 experiments. The results showed that the effect of the treatment temperature was more notable than time. The medium acidity (pH) variations in HTT can lead to the removal of extractives and starch, hemicelluloses hydrolysis, the destruction of the parenchymal cells wall, and weight loss. Based on the variance analysis, the quadratic and linear models proved to be highly significant with minimal probability values (< 0.0001). The optimum conditions predicted for the HTT were a pH of 7.3, a temperature of 112.7 °С, and a time of 109.6 min.