Modulating mechanotransduction by inhibiting yes-associated protein (YAP) in mice yields wound regeneration without scarring. However, rodents are loose-skinned and fail to recapitulate key aspects of human wound repair. We sought to elucidate the effects of YAP inhibition in red Duroc pig wounds, the most human-like model of scarring. We show that one-time treatment with verteporfin, a YAP inhibitor, immediately after wounding is sufficient to prevent scarring and to drive wound regeneration in pigs. By performing single-cell RNA sequencing (scRNA-seq) on porcine wounds in conjunction with spatial proteomic analysis, we found perturbations in fibroblast dynamics with verteporfin treatment and the presence of putative pro-regenerative/profibrotic fibroblasts enriched in regenerating/scarring pig wounds, respectively. We also identified differences in enriched myeloid cell subpopulations after treatment and linked this observation to increased elaboration of interleukin-33 (IL-33) in regenerating wounds. Finally, we validated our findings in a xenograft wound model containing human neonatal foreskin engrafted onto nude mice and used scRNA-seq of human wound cells to draw parallels with fibroblast subpopulation dynamics in porcine wounds. Collectively, our findings provide support for the clinical translation of local mechanotransduction inhibitors to prevent human skin scarring, and they clarify a YAP/IL-33 signaling axis in large animal wound regeneration.