Bergenin, which is isolated from <i>Bergenia</i> species, exhibits various pharmacological properties. In the search for new types of immunosuppressants, a series of bergenin derivatives were designed and synthesized, and their immunosuppressive effects were evaluated by the CCK-8 assay. The experimental data demonstrated that compounds <b>7</b> and <b>13</b> showed the strongest inhibition effects on mouse splenocyte proliferation (IC<sub>50</sub> = 3.52 and 5.39 μM, respectively). Further studies revealed that the inhibitory effect may come from the suppression of both IFN-γ and IL-4 cytokines. Alkylated derivatives of bergenin with <i>n</i>-hexyl and <i>n</i>-heptyl on the two phenolic hydroxyl groups showed better inhibitory activities. The hydrophobicity of bergenin derivatives, the configuration of the 4-OH in bergenin, and the ability to form hydrogen bonds of the substituents on the <i>C</i>-4 position are important to the immunosuppressive activity. This work proved that the modifications of bergenin may represent a new route to the discovery of a new class of immunosuppressive agents.