To excavate the bio-active compounds and potential molecular mechanism for the herb pair Caulis Trachelospermi and Herba Lycopodii on osteoarthritis (OA) based on the network pharmacology method.Methods:Known bioactive-ingredients of the of herb pair were obtained from the Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP) and the Shanghai Institute of Organic Chemistry of CAS，Chemistry Database (CASC) with their potential targets predicted by the Swiss Target Prediction server.Known OA-related genes were mined in disease databases; protein-protein interaction (PPI) network was constructed with the collected data，and their intersection was extracted as drug-disease interaction network; core gene targets were screened through network topology analysis.Kyoto Encyclopedia of Genes and Genomes signaling pathway analysis and Gene ontology analysis were performed to reveal gene function by DAVID database.Results:A total of 108 ingredients of two herbs were retrieved from the TCMSP and CASC databases and 17 of them are considered to be bio-active which yield 117 possible targets.191 OA-related targets were retrieved from the disease database.Network topology analysis of the Drug-disease interaction network yielded 208 core targets，which mainly enriched into inflammation，autophagy，and estrogen-related biological processes and pathways.Conclusion:The Caulis Trachelospermi-Herba Lycopodii herb pair may treat OA through adjusting inflammatory，autophagy and exerting estrogen-like effect，which embodied the multi-component，multi-target and multi-pathway synergy characteristics of traditional Chinese medicine，and provided ideas for further research.