Traumatic brain injury (TBI) is in part complicated by pro-oxidant iron elevation independent of brain hemorrhage. Ceruloplasmin (CP) and β-amyloid protein precursor (APP) are known neuroprotective proteins that reduce oxidative damage through iron regulation. We surveyed iron, CP and APP in post mortem control and TBI-affected brain tissue, which was stratified according to time of death following injury. We observed CP and APP induction following TBI accompanying iron accumulation. Elevated APP and CP expression was also observed in a mouse model of focal cortical contusion injury concomitant with iron elevation. To determine if changes in APP or CP were neuroprotective we employed the same TBI model on APP-/- and CP-/- mice and found that both exhibited exaggerated infarct volume and iron accumulation post injury. Evidence supports a regulatory role of both proteins in an iron defence system to oxidative damage after TBI, which presents as a tractable therapeutic target.