Objective: To use weighted gene co-expression network analysis (WGCNA) and molecular docking techniques to predict the mechanism of action of Huangqi Guizhi Wuwu decoction (HGWWD) in the treatment of osteoarthritis (OA) and to provide a bioinformatics basis for the clinical application of HGWWD in the treatment of OA. Methods: After searching the Gene Expression Omnibus (GEO) database, the GSE55235, GSE206848 and GSE55457 datasets were obtained. After merging and normalizing the GSE55235 and GSE206848 datasets, differentially expressed genes (DEGs) were screened, modules closely associated with OA were screened using a weighted gene co-expression network (WGCN) constructed using R software, and the common genes among DEGs and key module genes were imported into the Database for Annotation, Visualization and Integrated Discovery (DAVID) for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The active ingredients in HGWWD were retrieved through the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP), and a "drug-active ingredient-target" network was constructed using Cytoscape software. The GSE55457 dataset was used to verify and compare the expression differences in hub genes between different groups. AutoDock was used to conduct molecular docking of key genes and related active ingredients, and PyMOL and Discovery Studio were used for visual analyses. Results: A total of 1455 DEGs were screened in the merged dataset, including 574 upregulated genes and 881 downregulated genes. The key module contained 388 genes. A total of 47 pathways were obtained from the KEGG analysis. β-Sitosterol, kaempferol, β-carotene, stigmasterol, and quercetin were identified as the main compounds of HGWWD, and interleukin (IL)-6, prostaglandin-endoperoxide synthase 2 (PTGS2), vascular endothelial growth factor A (VEGFA), JUN, MYC, NFKBIA, SELE, and chemokine (C-X-C motif) ligand 2 (CXCL2) were the main hub genes involved in the treatment of OA with HGWWD. Molecular docking indicated that except for quercetin, the binding energies of other major compounds to hub genes were less than -5.0 kcal/mol. Conclusion: β-Sitosterol, kaempferol, β-carotene, stigmasterol and quercetin in HGWWD act on MYC, JUN, IL-6, VEGFA, and SELE, thus generating good therapeutic effects in individuals with OA.