Photodynamic therapy (PDT) has been shown to significantly inhibit fibroblast activity. However, the effect of PDT mediated by the photosensitizer hematoporphyrin monomethyl ether (HMME) on keloids is not known well. The aim of our study was to examine the efficacy of HMME-PDT in cellular and animal models of keloids. Keloid fibroblasts (KFbs) were isolated from human keloid specimens and the proliferation, invasion, and migration of KFbs after HMME-PDT treatment was examined in vitro. Apoptosis in cells was measured by flow cytometry. Cysteinyl aspartate specific proteinase 3 (Caspase3) expression was determined by immunofluorescence staining and western blot. HMME-PDT inhibited KFbs proliferation, invasion, migration, increased apoptosis rate and enhanced caspase3 and cleaved caspase3 expression. The keloid graft transplantation was performed by using nude mice. The growth of the graft was monitored every third day. Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) mRNA expression were detected by quantitative real time PCR. It was observed that HMME-PDT attenuated graft growth and reduced vessel density in the keloid grafts. However, HMME-PDT did not alter IL-6 and TNF-α mRNA expression in the keloid grafts. Moreover, HMME-PDT suppressed transforming growth-β1 (TGF-β1) and small phenotype and Drosophila Mothers Against Decapentaplegic 3 (Smad3) expression in both KFbs and keloid grafts. Collectively, the evidence suggests that HMME-PDT inhibits the growth of the keloid graft by promoting the apoptosis of fibroblasts and reducing vessel formation of the keloid graft.