In response to ER stress, the pancreatic endoplasmic reticulum kinase (PERK) coordinates an adaptive program known as the integrated stress response (ISR) by phosphorylating the α subunit of eukaryotic translation initiation factor 2 (eIF2α). IFN-γ, which activates the ER stress response in oligodendrocytes, is believed to play a critical role in the immune-mediated CNS disorder multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). Here we report that CNS delivery of IFN-γ before EAE onset ameliorated the disease course and prevented demyelination, axonal damage, and oligodendrocyte loss. The beneficial effects of IFN-γ were accompanied by PERK activation in oligodendrocytes and were abrogated in PERK-deficient animals. Our results indicate that IFN-γ activation of PERK in mature oligodendrocytes attenuates EAE severity and suggest that therapeutic approaches to activate the ISR could prove beneficial in MS.