Abstract: A series of polyurethane foams (PUF) based on poly(4-hydroxybutyrate) (P4HB) were synthesized via the prepolymer method under solvent-free conditions, using P4HB as the soft segment, diphenylmethane diisocyanate (MDI) and 1,4-butanediol (BDO) as the hard segments, and water as the blowing agent. The effects of catalyst and its dosage, surfactant amount, the ratio of n(―NCO)/n(―OH), hydroxyl value (OHV) of P4HB, NCO content of the prepolymer, and blowing agent dosage on the foaming process and PUF properties were systematically investigated. The obtained foams were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), uniaxial tensile tests, and vertical rebound measurements to evaluate their thermal, mechanical, and resilience properties. The optimal formulation was identified as an the ratio of n(―NCO)/n(―OH) = 1.1, a P4HB OHV of 56 mg KOH/g, the prepolymer’s NCO content of 6 wt%, and a blowing agent loading of 0.36 wt%. The obtained PUF exhibited a tensile strength up to 2.6 MPa, a tear strength of 13.9 kN/m, and a rebound rate of 33%, which were comparable to those of commercial MDI-based PUF shoe midsoles from Huafon Group Co., Ltd.