The mechanisms leading to oxidative stress and cellular dysfunction during stroke are not well understood. To test the hypothesis that transient cerebral artery occlusion (MCAo) in mice results in the generation of oxidized phospholipids (oxPLs) that contribute to neuronal cell death and glial activation. Both in vitro and in vivo cerebral ischemia and reperfusion injury (IRI) resulted in the elevation of specific oxPLs. Neuronal cell death was determined in the presence of oxPLs and the natural oxPL E06 antibody protected the cells from the toxic effects. IRI in mice gave rise to increased immunoreactivity of oxPLs in the brain. E06 reduced inflammatory markers in the brain following IRI, including iba-1, GFAP and inflammatory cytokines. In addition, oxPLs gave rise to M1 and Mox microglial phenotypes which was reversed in the presence of E06 and elicited a more M2 phenotype. Nrf2 deficient mice show increased infarct volumes and microglia from Nrf2 ^-/- mice show a reduction in Mox gene expression, and E06 protects both mice and cells from the Nrf2 deficit. Cerebral IRI generates oxPLs which triggers neuronal cell loss and inflammation and inactivation of oxPLs in vivo reduces infarct volume and improves outcomes.