It’s been reported that Mori Folium (MF) and Eucommiae Cortex (EC) exhibit pharmacological effects on the treatment of immunosuppression. However, the mechanism of MF and EC against immunosuppression remains unclear. This study aims to explore the mechanism of action of MF and EC for the treatment of immunosuppression through network pharmacology, molecular docking, molecular dynamics simulations and animal experiments. As a result, 11 critical components, 9 hub targets, and related-signaling pathways of treatment of immunosuppression were obtained based on network pharmacology. The molecular docking suggested that 11 critical components exhibited great binding affinity to 9 hub targets of immunosuppression. The molecular dynamics simulations results showed that (-)-Tabernemontanine-AR, beta-sitosterol-AR and Dehydrodieugenol-HSP90AA1 complexes are stably bound. Additionally, in the animal experiments, the treated group results compared to the control group suggest that MF and EC have a significant effect on the treatment of immunosuppression. Therefore, the MF and EC treatment for immunosuppression may take effects in a multi-component, multi-target, and multi-pathway manner. The results would provide novel insights into the treatment of immunosuppression in humans.