The detrimental effects of T-cell-secreted interferon gamma (IFNγ) on oxidative stress (OS) and demyelination in multiple sclerosis (MS) are well recognized. Recently, we demonstrated that IFNγ-mediated damage to myelin also increases susceptibility to spreading depression (SD; the likely basis of migraine with aura). However, before onset of MS, induction of physiological levels of IFNγ, like that produced by environmental enrichment (EE), protects against demyelination and OS. Accordingly, we focused on the potential for physiological levels of IFNγ to protect against SD. EE, which occurs with a moderate and phasic increase in proinflammatory cytokines, reduces migraine frequency. Thus, we applied phasic or pulsed IFNγ to brain slice cultures to emulate EE. This treatment reduced OS, increased myelin basic protein, a marker for myelin, and reduced susceptibility to SD. Building on our research on exosomes in EE-based neuroprotection, we found that IFNγ stimulation of slice cultures induced release of exosomes, likely from the microglia that produce the same protective effects as IFNγ treatment when applied to naive cultures. Finally, nasal administration of IFNγ to rats recapitulated in vitro effects, reducing OS, increasing myelin, and reducing SD. These results support phasic IFNγ signaling as a therapeutic target for prevention of SD and, by extension, migraine.