Multiple sclerosis (MS) is a common autoimmunity disease of the central nervous system (CNS) that mostly happens in young adults. The chronic clinical features of MS include inflammatory demyelination, infiltration of immune cells, and secretion of inflammatory cytokines, which have been proved to be associated with CD4⁺ T cells. Ferroptosis is a newly discovered programmed cell death mediated by the massive lipid peroxidation and more sensitive to CD4⁺ T cells. However, the effect of ferroptosis of CD4⁺ T cells on the occurrence and progression of MS retains unclear. Here, the experimental autoimmune encephalomyelitis (EAE) model was used to investigate the role of GPX4, a leading inhibitor of ferroptosis, which plays in the function of CD4⁺ T cells. Our results showed that GPX4 was highly expressed in CD4⁺ T cells of MS patients based on existing databases. Strikingly, conditional knockout of GPX4 in CD4^cre mice (cKO mice) significantly alleviated the average symptom scores and immunopathology of EAE. The infiltration of immune cells, including CD4⁺ T and CD8⁺ T cells, and the generation of GM-CSF, TNF-α, and IL-17A, were remarkably reduced in the CNS from cKO mice compared with WT mice. These findings further revealed the vital role of GPX4 in the expansion and function of CD4⁺ T cells. Moreover, GPX4-deficient CD4⁺ T cells were susceptible to ferroptosis in EAE model. Overall, this study provided novel insights into therapeutic strategies targeting GPX4 in CD4⁺ T cells for inhibiting CNS inflammation and treating MS.