Polyurethane (PU) foams have become an increasingly important research field due to their use in many areas, such as advanced polymer applications. Many factors affect PU quality during production, and the interaction of these factors with each other also directly affects product quality. For this reason, the study examined the factor effects on PU quality with a systematic design of the experiment and optimization approach. The isocyanate index had the greatest effect on selected quality criteria, such as indentation force deflection, hysteresis loss, wet and dry constant deflection compression, compression force deflection, flammability, and density, synergistically. The strongest interaction effect was from molding temperature and time, which reduced the PU density. Furthermore, optimal process conditions were specified by the desirability function approach as 96.41 (I/P) for isocyanate index, 43.31°C for molding temperature, and 2.15 min. for molding time. Cost-effective PU production with low density by the desired standard is possible.