Tripterygium wilfordii hook (TWH) has been used to treat Behcet’s disease (BD) but its underlying mechanism remains unclear. This study aims to explore the mechanism of TWH on BD using network pharmacology and molecular docking. The bioactive constituents of TWH and their corresponding target genes were extracted from the Traditional Chinese Medicine systems pharmacology database and analysis platform. BD target genes were obtained by searching the DisGeNet and GeneCards databases. Gene ontology annotation and Kyoto encyclopedia of genes and genomes pathway enrichment analysis were conducted to elucidate the function of overlapping genes between TWH and BD target genes. A protein-protein interaction network was constructed using Cytoscape and STRING platforms, and the core target genes were identified from the overlapping genes. Finally, molecular docking was used to assess the binding affinity between the core targets and TWH bioactive constituents. We identified 25 intersection genes related to both TWH and BD and 27 bioactive ingredients of TWH. Through analysis of protein-protein interaction network, 6 core targets (TNF, IFNG, prostaglandin-endoperoxide synthase 2, NOS2, VCAM-1, and interleukin-2) were screened out. Enrichment analysis demonstrated that the antioxidant properties of TWH constituents might play a significant role in their therapeutic effects. Molecular docking revealed high binding affinity between the bioactive constituents of TWH, such as kaempferol, triptolide, 5, 8-Dihydroxy-7-(4-hydroxy-5-methyl-coumarin-3)-coumarin, and their corresponding target genes, suggesting the potential of TWH to treat BD. Our investigation clarified the active components, therapeutic targets of BD in the treatment of TWH and provided a theoretical foundation for further researches.