The aim was to identify latent mechanism of BuShenHuoXue (BSHX) formula for the management of osteoarthritis (OA) through the network pharmacology approach and experimental validation. We obtained OA-related targets through the Gene Expression Omnibus database and bioactive ingredients with corresponding targets in the formula via the Traditional Chinese Medicine Systems Pharmacology database. Subsequently, networks of the protein-protein interaction and compound-disease target were created and enrichment analysis was implemented. Furthermore, in vitro, IL-1β was applied to rat chondrocytes to mediate apoptosis through inflammation and the Alcian blue and type II collagen staining was used to observe cell morphology. The TUNEL and DAPI staining was performed to observe chondrocyte apoptosis, and the apoptosis rates were gauged via flow cytometry. In addition, we utilized Western blot and PCR to detect the protein and mRNA expression, respectively. A total of 104 potential chemicals and 42 intersecting targets were screened out. Quercetin and luteolin from BSHX formula were principal ingredients. The experiment validated quercetin might suppress chondrocyte apoptosis mediated by IL-1β and reduce SELE, MMP2, and COL1 expression. Via the AGE-RAGE signaling pathway in diabetic complications, quercetin could aim at SELE, MMP2, and COL1 and exert antagonistic effects against OA.© 2022 The Authors. Published by American Chemical Society.