Biocompatible polymeric material with well-defined, interconnected porous structure plays an important role in many biomedical applications, such as tissue engineering, controlled drug release, biochemical sensing, and 3D cell culture for drug discovery. In this study, a novel fabrication process for porous polymer is developed using high intensity focused ultrasound. This acoustic method is solvent-free and capable of creating interconnected porous structures with varying topographical features at designed locations. An experimental study on the selective ultrasonic foaming technique is presented in this paper. We investigated the effects of major process variables, including ultrasound power, scanning speed, and gas concentration. Both pore size and interconnectivity of the created porous structures were examined. It was found that the pore size could be controlled with the scanning speed of the ultrasound insonation and that interconnected porous structures could be obtained using a partial saturation procedure. A concentration-dependent gas diffusion model was developed to predict the gas concentration profiles for partially saturated samples. A cell culture study was conducted to examine cell growth behavior in the fabricated porous structures.