Objective To investigate the effect of fractional CO? laser treatment on the repair of post-burn hypertrophic scars in mice and to explore the potential role of the TP53/MMP1 signaling axis in this process. Methods A mouse model of post-burn hypertrophic scarring was established in C57BL/6 mice and treated with fractional CO2 laser irradiation. Gross observation was performed to assess changes in scar area. Hematoxylin and eosin (H&E) staining was used to evaluate histomorphological alterations, and Masson’s trichrome staining was performed to assess collagen deposition and fiber organization. RT-qPCR and Western blotting were used to determine the mRNA and protein expression levels of Collagen I, Collagen III, α-SMA, TP53/p53, and MMP1 in scar tissues. In addition, lentiviral vectors were used to establish shTP53 and shTP53+oeMMP1 intervention models to evaluate the effects of TP53 knockdown and MMP1 overexpression on fractional CO2 laser-mediated scar repair. Results Compared with the control group, the model group exhibited increased cellular and fibrous tissue proliferation, epidermal thickening, and dense and disorganized collagen fibers. The mRNA and protein expression levels of Collagen I, Collagen III, and α-SMA were increased, with statistically significant differences (P<0.05). Compared with the model group, fractional CO2 laser treatment significantly reduced the relative residual wound area on days 7 and 14 (P<0.01), decreased epidermal thickness and collagen deposition, and improved collagen fiber organization. The mRNA and protein expression levels of Collagen I, Collagen III, and α-SMA were also decreased (P<0.05). TP53 mRNA expression was markedly decreased in the model group compared with the control group (P<0.0001), whereas p53 protein expression was significantly decreased (P<0.01). Following fractional CO2 laser treatment, both TP53 mRNA and p53 protein expression were increased compared with those in the model group (P<0.05). Under fractional CO2 laser treatment, TP53 mRNA expression was markedly decreased in the shTP53 group compared with the shNC group (P<0.0001), whereas p53 protein expression was decreased (P<0.05). MMP1 mRNA expression was significantly decreased (P<0.01), and MMP1 protein expression was also decreased (P<0.05). In addition, the relative residual wound area on days 7 and 14 was increased in the shTP53 group (P<0.05). The mRNA and protein expression levels of Collagen III were significantly increased (P<0.01), whereas those of Collagen I and α-SMA were increased (P<0.05). Compared with the shTP53 group, the shTP53+oeMMP1 group showed markedly increased MMP1 mRNA and protein expression (P<0.0001 and P<0.001, respectively), whereas no significant differences were observed in TP53 mRNA or p53 protein expression (P>0.05). The relative residual wound area on days 7 and 14 was decreased (P<0.05), accompanied by improved tissue architecture and reduced collagen deposition. Collagen I mRNA expression was significantly decreased (P<0.01), whereas Collagen III and α-SMA mRNA expression and Collagen I, Collagen III, and α-SMA protein expression were decreased (P<0.05). Conclusion Fractional CO2 laser treatment promotes the repair of post-burn hypertrophic scars in mice, improves scar tissue architecture, and reduces abnormal collagen deposition. These effects may be associated with upregulation of the TP53/MMP1 signaling axis and enhanced extracellular matrix remodeling.