T helper 17 (Th17) cells has proven to be crucial in the pathogenesis of severe asthma. Although it is known that Suppressor of cytokine signaling 3 (SOCS3) is involved in differentiation of Th17 cells but, how it affects severe asthma is uncertain. Since previous studies indicated that Methtyl-CpG binding domain protein 2 (MBD2) null mice was deficient in Th17 cell differentiation, the aim of the present study was to understand how MBD2 interacts with SOCS3 to regulate Th17 cell differentiation in severe asthma. Here, we show that SOCS3 expression was significantly decreased in Th17-mediated severe asthmatic mice, accompanied by elevated STAT3 phosphorylation and RORγt expression. Knock-down of SOCS3 promoted the differentiation of na?ve T cells into Th17 cells through STAT3/RORγt pathway. Meanwhile, MBD2 was overexpressed in Th17-mediated severe asthmatic mice. Intervention of MBD2 expression lead to a negative change of SOCS3 expression, whereas the differentiation of Th17 cells showed positive change. In addition, MBD2 knockout (MBD2-KO) mice displayed increased SOCS3 expression and decreased Th17 differentiation after severe asthma modeling. Taken together, our results suggest that MBD2 might facilitate Th17 cell differentiation via down-regulating SOCS3 expression in severe asthma. These findings uncover new roles for SOCS3 and MBD2, and provide a potential target for treatment of severe asthma.