Psoriasis is a chronic inflammatory skin disease, primarily caused by overgrowth and abnormal differentiation of epidermal keratinocytes. Studies have suggested that keratinocyte growth factor (KGF) may be involved in the regulation of differentiation and development of keratinocytes. Total glucosides of peony (TGP) have been widely used for the treatment of psoriasis. The present study aimed to determine whether the therapeutic effect of TGP on psoriasis is mediated by modulation of the p38 mitogen‑activated protein kinase (p38 MAPK)/nuclear factor (NF)‑κB p65 signaling pathways. Cell proliferation was evaluated by CCK‑8 and cell cycle was assessed by flow cytometry assay. Protein and mRNA expression of genes were determined by western blot and reverse transcription‑quantitative polymerase chain reaction, respectively. The results of the present study demonstrated that KGF can promote proliferation of HaCaT cells in a dose‑dependent manner. In addition, it was demonstrated that TGP may suppress the hyperproliferation of HaCaT cells stimulated by KGF by inducing arrest of the cell cycle at the G1 phase. The expression levels of the proinflammatory cytokines interleukin (IL)‑22 and vascular endothelial growth factor (VEGF) were markedly elevated in cells treated with KGF, whereas they were downregulated in cells treated with TGP. Furthermore, combination treatments with p38 MAPK inhibitor SB203580 and KGF, or TGP and KGF suppressed the mRNA and protein expression levels of IL‑22 and VEGF, compared with cells treated with KGF alone. Furthermore, the expression profiles of phosphorylated‑p38 MAPK and NF‑κB p65 were similar to those of IL‑22 and VEGF. The results of the present study suggested that the therapeutic effect of TGP on psoriasis may be mediated by modulation of the p38 MAPK/NF‑κB p65 signaling pathway. The results of the present study contribute to the understanding of the role of TGP in the treatment of psoriasis. The present study provides insights suggesting that p38 MAPK may be a novel regulatory signaling pathway for the treatment of psoriasis.