Traumatic brain injury (TBI) is a significant global health issue, characterized by high rates of morbidity and mortality, along with substantial economic strains on healthcare systems. This study explores the potential of Aminophylline (AMP), a medication traditionally used for cardiovascular conditions and bronchiectasis, to enhance TBI outcomes by protecting against neuronal damage. Our findings indicate that AMP treatment significantly reduces neuronal ferroptosis in the cortex, leading to less tissue damage and notable improvements in cognitive and motor functions in mice subjected to controlled cortical impact (CCI). Additionally, we found that TBI resulted in decreased expression of miR-128-3p, a reduction that was further strengthened by AMP treatment. Gain-of-function experiments showed that overexpressing miR-128-3p increases neuronal ferroptosis by targeting Slc7a11, indicating how AMP mitigates cognitive and motor impairments in CCI mice. This study highlights the potential of AMP in treating TBI through the miR-128-3p/Slc7a11 pathway, marking the first report of its protective effects against ferroptosis in TBI.