Traumatic brain injury often causes poor outcomes and has few established treatments. Neuroinflammation and ferroptosis hinder therapeutic progress in this domain. Annexin A5 (A5) has anticoagulant, anti-apoptotic and anti-inflammatory bioactivities. However, its protective effects on traumatic brain injury remain unclear. Thus, we explored whether inhibiting ferroptosis and neuroinflammation using A5 could ameliorate traumatic brain injury. We injected recombinant A5 (50 µg/kg) in the tail vein of mice 30 min after fluid percussion injury. We then assessed modified neurologic severity scores, Morris water maze performance, rotarod test performance, brain water content, and blood-brain barrier permeability to document the neuroprotective effects of A5. Two days after the traumatic brain injury, we collected injured cortex tissues for western blot, Perl's staining, apoptosis staining, Nissl staining, immunofluorescence/immunohistochemistry, and enzyme-linked immunosorbent assay. We also quantified superoxide dismutase and glutathione peroxidase activity and glutathione and malondialdehyde levels. A5 improved neurological deficits, weight loss, cerebral hypoperfusion, brain edema, blood-brain barrier disruption, neuronal apoptosis, and ferroptosis. It also increased the ratio of M2/M1 phenotype microglia, reduced interleukin 1β and 6 levels, decreased peripheral immune cell infiltration, and increased interleukin 10 levels. A5 reduced neuronal iron accumulation, p53-related cell death, and oxidative stress damage. Finally, A5 downregulated HMGB1 and NF-ĸB pathways and upregulated the nuclear erythroid 2-related factor (Nrf2) and HO-1 pathways. These results suggest that A5 exerts neuroprotection in traumatic brain injury mice and ameliorates neuroinflammation, oxidative stress, and ferroptosis by regulating the NF-kB/HMGB1 pathway and the Nrf2/HO-1 antioxidant system.