Abstract: OBJECTIVE To explore the potential pharmacodynamic components and molecular mechanism of Huoluo pill in the treatment of osteoarthritis by using computer aided drug design and network pharmacology based on the pathogenesis of osteoarthritis and the need for clinical drugs. METHODS TCMSP, TCMID and Chemistry database were used to search the traditional Chinese medicine compounds of Huoluo pill. The affinity of compounds for therapeutic targets of osteoarthritis such as COX-2, 5-LOX and coagulation factor F2 was evaluated by molecular docking and binding free energy calculations. The hierarchical clustering and pharmacophore model of potential active compounds were constructed. Swiss Target Prediction was used to predict the potential targets of compounds. Cytoscape constructed a network of "drug flavor-component-potential target". Genecards, DrugBank, TTD and CTD databases were used to search for osteoarthritis targets. DAVID performed GO and KEGG analyses, and STRING analyzed the target protein interactions.RESULTS The components with potential affinity for therapeutic targets of osteoarthritis such as COX-2, 5-LOX and coagulation factor F2 were obtained. The pharmacop was constructed after hierarchical cluster analysis, and the pharmacophore models AAH, AAA and AAR for COX-2, 5-LOX and F2 were obtained by molecular docking and binding free energy calculation. The skeleton structure represented by santamarine, aloe emodin and glabridin might had potential effect on the treatment of osteoarthritis. There were 180 targets in Huoluo pill and osteoarthritis. Through PPI analysis, 179 potential targets such as STAT3, SRC, CXCR4 and EP300 were obtained. Six hundred and eighty six GO items and one hundred and eight KEGG pathways were obtained through GO and KEGG analyses. CONCLUSION In this study, arachidonic acid metabolic targets COX-2, 5-LOX and coagulation target F2 are selected. Through multi-target molecular docking and binding free energy calculation step by step screening, cluster analysis, pharmacophore model and network pharmacology, the molecular mechanism of "multi-point effect and synergistic effect" of Huoluo pill is preliminarily revealed. It provides target combination and research basis for the development of active Chinese medicine components or component compatibility with osteoarthritis with low potential adverse reactions.