【Objective】 To explore the mechanism of Yougui Pills in the treatment of knee osteoarthritis （KOA） based on network pharmacology and molecular docking. 【Methods】 The active components of Yougui Pills were obtained by searching TCMSP database. With the active component targets predicted by TCMSP， SwissTargetPrediction and TargetNet， we searched TCMIP， CTD， DisGeNET and GeneCards databases for KOA related targets. By crossing the two sets of targets， we obtained therapeutic targets of Yougui Pills for KOA. FDA-approved drugs for KOA and their targets were searched in the DrugBank database， and the drug-target network was constructed by using Cytoscape. Then the protein-protein interaction （PPI） network was constructed by using STRING database. After Go and KEGG enrichment analyses， the network of “traditional Chinese Medicine-active components-key targets-significant pathways-biological process” was constructed. 【Results】 A total of 132 active components were obtained from the nine herbal medicines of Yougui Pills， corresponding to 490 targets， of which 76 were potential therapeutic targets. Of them 13 were the same as the targets of 5 Western medicines for KOA. We screened out 18 key targets by the PPI network. Go enrichment analysis revealed 1281 biological processes， 60 molecular functions， and 17 cellular components， which were mainly related to inflammation， infection and oxidative stress. KEGG enrichment analysis showed that 50 pathways were significantly enriched， including IL-17 signaling pathway and TNF signaling pathway， whose functions were mainly involved in immune system， signal transduction， endocrine system， cell growth and death and other biological processes. 【Conclusion】 With multiple compounds acting on multiple molecular targets， Yougui Pills can treat KOA through molecular mechanisms including inhibiting inflammation， reducing oxidative stress， and promoting cartilage cell proliferation.