The heart-lung machine has commonly been used to replace the functions of both the heart and lungs during open heart surgeries or implemented as extracorporeal membrane oxygenation (ECMO) to provide cardiopulmonary support of the heart and lungs. The traditional heart-lung system consists of multiple components and is bulky. It can only be used for relatively short-term support. The concept of the wearable artificial pump-lung is to combine the functions of the blood pumping and gas transfer in a single, compact unit for cardiopulmonary or respiratory support for patients suffering from cardiac failure or respiratory failure, or both, and to allow patients to be ambulatory. To this end, a wearable artificial lung (APL) device is being developed by integrating a magnetically levitated centrifugal impeller with a hollow fiber membrane bundle. In this study, we utilized a computational fluid dynamics based performance optimization with a heuristic scheme to derive geometrical design parameters for the wearable APL device. The configuration and dimensions of the impeller and the diffuser, the required surface area of fiber membranes and the overall geometrical dimensions of the blood flow path of the APL device were considered. The design optimization was iterated based on the fluid dynamic objective parameters (pressure head, pressure distribution, axial force acting on the impeller, shear stress), blood damage potential (hemolysis and platelet activation), and mass transfer (oxygen partial pressure and saturation). Through the design optimization, an optimized APL device was computationally derived. A physical prototype of the designed APL device was fabricated and tested in vitro. The experimental data showed that the optimized APL can provide adequate blood pumping and oxygen transfer over the range of intended operating conditions.