Targeting regulatory T (Treg) cells represents a promising strategy for reshaping peripheral immune homeostasis and treating inflammatory diseases, such as inflammatory bowel disease and multiple sclerosis. However, the two main strategies used for targeting Treg cells, which include adoptive Treg cell therapy and low-dose interleukin (IL)-2 treatment, have not achieved satisfactory clinical outcomes. Multiple studies have indicated that targeting Treg cells alone cannot effectively restore immune homeostasis. Here, we showed that the combination of low-dose IL-2 therapy and inhibition of IL-6/STAT3 signaling exhibits better therapeutic effects in the treatment of inflammatory bowel disease and experimental autoimmune encephalomyelitis. This combination therapy restored immune homeostasis and alleviated inflammation by significantly increasing Treg cells and suppressing effector T cells, such as T helper 1 and T helper 17 cells. Overall, our data indicate that the combination of low-dose IL-2 therapy and inhibition of IL-6/STAT3 signaling warrants further investigation as a means of remodeling immune homeostasis to treat mucosal inflammation and autoimmune disorders.