Background and Purpose: Psoriasis is an immune-associated disease, however, the pathogenesis of psoriasis remains unclear. We investigated the mechanism of IL-35 in psoriasis treatment. Experimental Approach: PASI and Baker scores were used to evaluate the Imiquimod-induced psoriasis mouse model. Flow cytometry is used to detect changes in immune cells and to select target cells. The changes of inflammatory factors were detected by ELISA. Adoptive transfused was used to demonstrate the effect of the corresponding cells. Key Results: IL-35 expression in patients with psoriasis was significantly increased. The number of myeloid-derived suppressor cells (MDSCs) in patients was also significantly increased. Similar results were obtained in mice with imiquimod (IMQ)-induced psoriasis. IL-35 had potent immunosuppressive effects on psoriasis model mouse, leading to a decrease in the total number of MDSCs and its subtypes in the spleen and psoriatic skin lesions. The level of inducible nitric oxide synthase (iNOS) secreted by MDSCs also decreased significantly; however, there was no difference in the level of IL-10 in MDSCs. Adoptive transfer of MDSCs from IMQ-challenged mice weakened the effect of IL-35. When MDSCs were isolated from iNOS knockout mice that were established with IMQ and transfected into IMQ-induced WT mice, there was no significant difference in psoriasis area and severity index scores between IL-35 + iNOS-/–MDSC and IL-35 treatment groups. Conclusions and Implications: IL-35 plays an important immunosuppressive role in psoriasis by inhibiting the counts of MDSCs expressing iNOS. This study may serve as a new therapeutic strategy for patients with chronic psoriasis or other cutaneous inflammatory diseases.