OBJECTIVE: To identify the main active components and targets of Huashi Xingyu Qingre recipe (HXQR) and to investigate its mechanism in the treatment of oral lichen planus (OLP). METHODS: The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform was searched to identify the active ingredients and corresponding targets of HXQR. Disease genes were obtained from the GeneCards database, and a "drug-disease regulatory network" was constructed using Cytoscape software and PERL programming language. The STRING database was used to build a protein- protein interaction network. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms were analyzed using R software with a Bioconducter plugin. Finally, the results and the efficacy of HXQR in treating OLP were validated in a clinical trial that included enzyme-linked immunosorbent assay (ELISA) testing and observations of the post-treatment changes in clinical symptoms. RESULTS: HXQR contained 167 active components and 261 targets, with 391 disease targets. The intersection of these two categories in a Venn diagram revealed 57 drug-disease common targets. A compound-target network was constructed and revealed that the six key pharmaceutical ingredients of HXQR were quercetin, luteolin, wogonin, kaempferol, beta-carotene, and baicalein. The protein-protein interaction network mainly involved core proteins such as ALB, interleukin-6, and AKT1. Drug-disease common targets were enriched in 1628 GO terms and 117 KEGG terms, mainly involving inflammatory responses, viral infections, and tumor-related pathways. ELISA testing indicated that HXQR inhibited the tumor necrosis factor (TNF) signaling pathway by reducing the expression of interleukin-6, matrix metalloproteinase-9, and intercellular adhesion molecule-1. The clinical symptoms of the patients with OLP were significantly improved after 8 weeks of treatment with HXQR. CONCLUSION: HXQR treats OLP by regulating the TNF signaling pathway, resulting in a marked treatment effect with few adverse effects. (C) 2022 JTCM. All rights reserved.