BACKGROUND: Common chronic wounds include diabetic ulcers, venous ulcers, and pressure ulcers. The traditional Chinese medicine Huiyang Shengji decoction (HYSJD) has been shown to promote the healing of diabetic chronic wounds, however, its pharmacological mechanism is still unclear. PURPOSE: This study aimed to determine the mechanism of HYSJD in promoting the healing of diabetic chronic skin ulcers. METHODS: Ultra-performance liquid chromatography was combined with tandem mass spectrometry (UPLC-MS/MS) to analyze the main components of HYSJD and the absorbed components in mouse serum at 30 min after oral administration of HYSJD. db/db mouse models for chronic skin ulcers were constructed by full-thickness skin resection. Wound tissues at day 7 post wound formation were used to perform microarray analysis of growth factors and chemokine expression. GO and KEGG enrichment analysis was performed on differentially expressed proteins. ELISA assays were used to measure differential expressed cytokines in the serum and Western blot analysis was used to determine the expression levels of related pathway proteins in the skin wounds. RESULTS: UPLC-MS/MS analysis showed that the main chemical components of HYSJD were flavonoids, terpenes, alkaloids, phenylpropanoids, and carbohydrates. At 30 min after oral administration of HYSJD, five absorbed components were detected in the serum, these included formononetin, calycosin, hypaconitine, calycosin-7-glucoside, and sinapic acid. HYSJD was found to increase the wound healing rate in chronic skin ulcers in db/db mice at days 3, 7, and 14 post wound formation, and promote the proliferation of epidermal cells. Two proteins that were differentially expressed between the different groups, i.e., IGF-1 and EGFR, were further validated. Serum ELISA assays showed that serum EGFR in the HYSJD treatment group was significantly increased. KEGG pathway analysis suggested that the PI3K/AKT pathway involved in HYSJD promoting the proliferation of epidermal cells in chronic wounds in db/db mice. Experimental verification showed that HYSJD activated the PI3K/AKT signaling pathway in mouse wound skin. CONCLUSION: HYSJD promotes the proliferation of epidermal cells in chronic diabetic wounds by increasing EGFR expression in the wounds and activating the PI3K/AKT signaling pathway. Our study provides an experimental basis for the pharmacological mechanism of HYSJD. CI - (c) 2021. The Author(s).