Bio-based polyurethane (BPU) foams were successfully prepared using hydrothermally liquefied wheat straw (WS) to substitute a mass fraction of up to 50% of polyols. Response surface methodology (RSM) based on central composite design (CCD) was employed to optimize four process parameters: NCO/OH molar ratio, loading of crosslinking agent (glycerol), loading of catalyst (a mixture of triethylene diamine, stannous octoate, and triethanolamine), and loading of blowing agent (water) for the maximum compression strength of the rigid BPU foams. With the quadratic orthogonal regression model, verified by experimentation, the maximum compression strength of approximately 180 kPa was obtained at the following optimal conditions: NCO/OH molar ratio of 1.24:1, glycerol addition of 12.11%, catalyst loading of 0.76%, and blowing agent addition of 1.31% in relation to the total mass of polyols. The BPU foam prepared at the optimal conditions exhibits good thermal conductivity (0.045 Wm(-1)K(-1)) and thermal stability, comparable to those of a reference foam prepared with 100% PPG400.