Thermoplastic polyurethane (TPU) is a versatile polymer with unique characteristics such as flexibility, rigidity, elasticity, and adjustable properties by controlling its soft and hard segments. To properly design and understand the TPU foaming process through supercritical CO2, a design of experiments approach, the Box–Behnken design (BBD) was adopted using commercial TPU 85A as the model compound. The effect of saturation pressure, saturation temperature, and immersion time on the mean pore size and expansion ratio were investigated. The design space for the production of TPU foam was shown, and the significance of process parameters was confirmed using the analysis of variance (ANOVA). In addition, extrapolation foaming experiments were designed and validated the feasibility of the response surface model developed via BBD. It was found that the pore size of TPU 85A foam could be controlled within 13 to 60 μm, and a stable expansion ratio could be designed up to six.