Objective: To determine the therapeutic effects of silybin (SBI) and its synergistic effects with mesenchymal stem cells (MSCs) in a lupus mouse model and to explore the therapeutic mechanisms. Methods: TLR7/8 agonist resiquimod (R848) was applied for the induction of lupus mice. R848-induced B6 mice were randomly divided into a normal saline control group, SBI group, MSCs group, and SBI plus MSCs group, and treated with daily SBI by gavage or received MSCs injection once via the tail vein. Mice were sacrificed at week 12, with urine, serum, kidney, and spleen collected. The proportion of cell subsets was detected by flow cytometry using splenocytes. Results: SBI treatment significantly decreased total IgG, anti-ds-DNA antibody, and urinary protein levels, as well as renal IgG and C3 deposition in R848-induced mice. It also increased the ability of MSCs to suppress splenomegaly and serum antinuclear antibody levels. In vivo and in vitro studies showed a decrease in the percentage of Tfh cells after SBI treatment, which was most pronounced when combined with MSC therapy. When splenocytes of R848-induced mice were treated with SBI and MSCs in vitro, the expression of genes related to Tfh cell differentiation, including IL-6, Stat3, and Bcl-6, was reduced, and the phosphorylation of AKT, S6, and STAT3 proteins in Tfh cells was decreased. Conclusion: SBI acts synergistically with MSCs to ameliorate lupus-like features in R848-induced mice. It may enhance the ability of MSCs to inhibit Tfh cell production by counteracting the activation of IL-6 and its downstream pathways.