Mechanical ventilation and extracorporeal membrane oxygenation are the only immediate options available for patients with respiratory failure. However, these options present significant shortcomings. To address this unmet need for respiratory support, innovative respiratory assist devices are being developed. In this study, we present the computational model-based design, and analysis of functional characteristics and hemocompatibility performance, of an innovative wearable artificial pump-lung (APL) for ambulatory respiratory support. Computer-aided design and computational fluid dynamics (CFD)-based modeling were utilized to generate the geometrical model and to acquire the fluid flow field, gas transfer, and blood damage potential. With the knowledge of flow field, gas transfer, and blood damage potential through the whole device, design parameters were adjusted to achieve the desired specifications based on the concept of virtual prototyping using the computational modeling in conjunction with consideration of the constraints on fabrication processes and materials. Based on the results of the CFD design and analysis, the physical model of the wearable APL was fabricated. Computationally predicted hydrodynamic pumping function, gas transfer, and blood damage potential were compared with experimental data from in vitro evaluation of the wearable APL. The hydrodynamic performance, oxygen transfer, and blood damage potential predicted with computational modeling, along with the in vitro experimental data, indicated that this APL meets the design specifications for respiratory support with excellent biocompatibility at the targeted operating condition.