Immune dysregulation in systemic autoimmune diseases, such as Sjögren’s syndrome (SS), rheumatoid arthritis and systemic lupus erythematosus has been recognized as the imbalance of regulatory to effector cell subsets. Taking SS as example, our studies have first revealed the defective IL-10-producing capacity in regulatory B (Breg) cells in both humans and murine model, which was critically involved in T cell homeostasis. However, seldom therapeutic agents targeting Breg cells are available to treat those autoimmune diseases. Previous studies have shown therapeutic effects of ethnic medicine on patients with SS. We have identified that acteoside (AC), a caffeoyl phenylethanoid glycoside from a medicinal herb Radix Rehmanniae, could promote IL-10 production from both human and murine B cells via critically regulating the TLR4/PI3K axis. Moreover, TLR4 was found increased in Breg cells from mice with experimental SS (ESS), a mouse model that recapitulates human SS. Thus, B cells from the ESS mice were susceptible to AC treatment, showing higher IL-10-producing capacity than those from naive controls. Notably, we found that AC was able to enter lymphoid organs upon oral administration. AC treatment effectively increased IL-10+ B cells in ESS mice and ameliorated disease pathology accompanied by reduced T effector cells, including Th17 and T follicular helper cells in the ESS mice. In conclusion, AC could promote Breg cell function and attenuate ESS pathology in vivo, which may be a promising drug candidate for treating SS and other autoimmune diseases.