Isoflurane is frequently employed as an inhalation anesthetic in pediatric medicine. The research found that repeated exposure to isoflurane had adverse effects on neurodevelopment. Despite the elusive nature of the underlying mechanisms, dimethyl fumarate (DMF) has been recognized as a biologically active compound with neuroprotective properties. This study examines the protective effects and underlying mechanisms of DMF both in vivo and in vitro against cognitive dysfunction in mice induced by repeated exposure to isoflurane. DMF treatment ameliorated cognitive dysfunction in mice subjected to isoflurane, alleviating neuronal and myelin injury and abnormal astrocyte death. In vitro studies demonstrated that DMF enhanced antioxidant enzyme activities, mitigated cellular oxidative stress, and improved mitochondrial function in cells exposed to isoflurane. Overall, we found that DMF alleviates cognitive impairment resulting from repeated isoflurane exposure. This effect is mediated through the hydrolytic metabolism of DMF, which enhances cellular energy production, activates the kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, reduces intracellular oxidative stress, and increases cellular antioxidant levels.