Much of our understanding of human biology and the function of mammalian cells in tissue regeneration have been derived from mechanistically and genetically manipulated rodent models. However, current models examining epidermal wound repair fail to address both the cross-species mechanistic and immunogenic differences simultaneously. Herein, we describe a multifaceted approach intended to better recapitulate human skin recovery in rodent models. First, immunodeficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice were intravenously inoculated with human hematopoietic stem cells to become, in essence, humanized, and capable of initiating an adaptive immune response. Next, a chimney-shaped mechanical device was implanted onto the excisional wound site to prevent healing by primary intention (contraction) and expedite cell transplantation. Subsequently, cell therapy was administered by transplanting cord blood-derived endothelial progenitor cells or human pluripotent stem cell-derived endothelial cells into the wound site to examine the regeneration process at a histological level. This study demonstrates human cutaneous repair in a murine model by addressing both the mechanistic and immunogenic differences in the epidermis. We further show human leukocyte recruitment in damaged tissue and improved healing by secondary intention in the transplanted groups, highlighting the need for useful preclinical animal models to better understand leukocyte function in human (tissue repair and) regeneration.