Ischemic stroke, a neurological condition with a complicated etiology that is accompanied by severe inflammation and oxidative stress, and ethanol (EtOH) may aggravate ischemia/reperfusion (I/R)-induced brain damage. However, the effect of prolonged alcohol intake on acute brain injury remains ambiguous. As part of the mitogen-activated protein kinase (MAPK) family, p38γ is involved in ferroptosis and inflammation in various diseases. This study explored how p38γ is involved in the effects of chronic EtOH consumption and brain injury caused by cerebral I/R. Brain damage was induced in the mice via the administration of a liquid alcohol-containing diet for 8 weeks, middle cerebral artery occlusion reperfusion (MCAO/R), or a combination of both. We verified that EtOH significantly exacerbated MCAO/R-induced brain damage, ferroptosis and inflammation. Notably, p38γ levels were increased in experimental mouse and cell models. p38γ knockdown markedly attenuated brain tissue damage, oxidative stress, and inflammatory cell infiltration in EtOH + MCAO/R-treated mice. Mechanistic experiments revealed that p38γ may regulate inflammation and ferroptosis through the p53/SLC7A11 pathway. Overall, our experimental results indicate that p38γ is crucial for regulating EtOH- and I/R-induced brain damage by modulating the p53/SLC7A11 pathway.