Objective: Xenografts of human skin on immunodeficient mice provide a means of assessing human skin physiology and its response to wounding. Approach: We describe a novel xenograft model using full-thickness human neonatal foreskin to examine human skin wound repair and fibroblast heterogeneity. Full-thickness 8-mm human neonatal foreskin biopsies were sutured into the dorsum of NSG (NOD.Cg-Prkdc scidIl2rgtm1Wjl/SzJ) pups as subcutaneous grafts and exposed to cutaneous grafts at the time of weaning (postnatal day 21). To model fibrosis, xenografts were wounded with 5-mm linear incisions and monitored until post-wound day (PWD) 14. To explore whether our model can be used to test the efficacy of topical therapies, wounded xenografts were injected with fibroblast growth factor-2 (FGF2) for the first four consecutive PWDs. Xenografts were harvested for analysis by histology and fluorescence-activated cell sorting (FACS). Results: Xenografts successfully engrafted with evidence of mouse-human anastomoses and resembled native neonatal foreskin at the gross and microscopic level. Wounded xenografted skin scarred with human collagen and an expansion of CD26-positive human fibroblasts. Collagen scar was quantitated by neural network analysis, which revealed distinct clustering of collagen fiber networks from unwounded skin and wounded skin at PWD7 and PWD14. Collagen fiber networks within FGF2-treated wounds at PWD14 resembled those in untreated wounded xenografts at PWD7, suggesting that FGF2 treatment at time of wounding can reduce fibrosis. Innovation and Conclusion: This novel xenograft model can be used to investigate acute fibrosis, fibroblast heterogeneity, and the efficacy of antifibrotic agents during wound repair in human skin.