Experimental autoimmune encephalomyelitis (EAE) is generally believed to be an autoimmune disease of the central nervous system (CNS) caused by myelin‐specific Th1 and/or Th17 effector cells. The underlying cellular and molecular mechanisms, however, are not fully understood. Using mice deficient in IL‐9 (IL‐9^−/−), we showed that IL‐9 plays a critical role in EAE. Specifically, IL‐9^−/− mice developed significantly less severe EAE than their WT counterparts following both immunization with myelin proteolipid protein (PLP)_180–199 peptide in the presence of Complete Freund's Adjuvant (CFA), and adoptive transfer of PLP_180–199 peptide‐specific effector T cells from WT littermates. EAE‐resistant IL‐9^−/− mice exhibited considerably fewer infiltrating immune cells in the CNS, with lower levels of IL‐17 and IFN‐γ expression, than their WT littermates. Further studies revealed that null mutation of the IL‐9 gene resulted in significantly lower levels of PLP_180–199 peptide‐specific IL‐17 and IFN‐γ production. Moreover, IL‐9^−/− memory/activated T cells exhibited decreased C–C chemokine receptors (CCR)2, CCR5, and CCR6 expression. Interestingly, IL‐10 was significantly increased in IL‐9^−/− mice compared with WT littermates. Importantly, we found that IL‐9‐mediated Th17‐cell differentiation triggers complex STAT signaling pathways.