Tumor necrosis factor-alpha (TNF-α) is a cytokine that plays an important role in inflammatory process and tumor development. Recent studies demonstrate that triterpene saponins from Vietnamese ginseng are efficient inhibitors of TNF-α. But the interactions between TNF-α and the saponins are still unclear. In this study, molecular docking and molecular dynamics simulations of TNF-α with three different triterpene saponins (majonoside R2, vina-ginsenoside R1 and vina-ginsenoside R2) were performed to evaluate their binding ability. Our results showed that the triterpene saponins have a good binding affinity with protein TNF-α. The saponins were docked to the pore at the top of the “bell” or “cone” shaped TNF-α trimer and the complexes were structurally stable during 100 ns molecular dynamics simulation. The predicted binding sites would help to subsequently investigate the inhibitory mechanism of triterpene saponins.