The S100A2 protein is an important regulator of keratinocyte differentiation, but its role in wound healing remains unknown. We establish epithelial-specific S100A2 transgenic (TG) mice and study its role in wound repair using punch biopsy wounding assays. In line with the observed increase in proliferation and migration of S100A2-depleted human keratinocytes, mice expressing human S100A2 exhibit delayed cutaneous wound repair. This was accompanied by the reduction of re-epithelialization as well as a slow, attenuated response of Mcp1, Il6, Il1β, Cox2, and Tnf mRNA expression in the early phase. We also observed delayed Vegfa mRNA induction, a delayed enhancement of the Tgfβ1-mediated alpha smooth muscle actin (α-Sma) axis and a differential expression of collagen type 1 and 3. The stress-activated p53 tumor suppressor protein plays an important role in cutaneous wound healing and is an S100A2 inducer. Notably, S100A2 complexes with p53, potentiates p53-mediated transcription and increases p53 expression both transcriptionally and posttranscriptionally. Consistent with a role of p53 in repressing NF-κB-mediated transcriptional activation, S100A2 enhanced p53-mediated promoter suppression of Cox2, an early inducible NF-κB target gene upon wound injury. Our study thus supports a model in which the p53-S100A2 positive feedback loop regulates wound repair process.