We demonstrated that a composite nanofibrous scaffold composed of PCL and native porcine liver ECM components enabled enhanced metabolic activities of HepaRG hepatocytes compared to conventional 2D cultures. Combined with a modular 3D-printed holder device fitting in a standard 12-well plate, this hepatic model can easily be integrated into existing cell culture workflows. With this 3D cell culture model, we tested well-documented drugs with in vivo data and found that the 3D model significantly enhanced drug clearance vs. the 2D well-plate model. More importantly, the drug clearance times and rates on our model were comparable with published in vivo data without significant differences. This 3D model thus holds promises to facilitate hepatocyte studies during preclinical drug development, especially given that it reproduced the in vivo observations with a widely accessible cell source (HepaRG), rather than primary human hepatocytes or stem cells.