Electroconvulsive therapy is highly effective in neuropsychiatric disorders by unknown mechanisms. Microglial toxicity plays key role in neuroinflammatory and degenerative diseases, where there is critical shortage in therapies. This study examined the effects of electroconvulsive seizures (ECS) on chronic neuroinflammation and microglial neurotoxicity.Electric brain stimulation inducing full tonic-clonic seizures during chronic relapsing-progressive experimental autoimmune encephalomyelitis (EAE) reduced spinal immune cell infiltration, reduced myelin and axonal loss, and prevented clinical deterioration. Using the transfer EAE model we examined the effect of ECS on systemic immune response in donor mice versus ECS effect on CNS innate immune activity in recipient mice. ECS did not affect encephalitogenicity of systemic T cells, but targeted the CNS directly to inhibit T-cell induced neuroinflammation. In vivo and ex-vivo assays indicated that ECS suppressed microglial neurotoxicity, by reducing iNOS expression, nitric oxide and reactive oxygen species (ROS) production, and by reducing CNS oxidative stress. Microglia from ECS treated EAE mice expressed less T cell stimulatory and chemoattractant factors. Our finding indicate that Electroconvulsive therapy targets the CNS innate immune system to reduce neuroinflammation by attenuating microglial neurotoxicity. These findings signify a novel therapeutic approach for chronic neuroinflammatory, neuropsychiatric and neurodegenerative diseases.