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Traumatic brain injury (TBI) is the most important cause of disability in individuals under the age of 45 years and thus represents a significant social and economic burden. Evidence strongly suggests that oxidative stress is a cornerstone event leading to and propagating secondary injury mechanisms such as excitotoxicity, mitochondrial dysfunction, apoptosis, autophagy, brain edema, and inflammation. TBI has defied conventional approaches to diagnosis and therapy development because of its heterogeneity and complexity. Therefore, it is necessary to explore alternative approaches to therapy development for TBI. The aim of this review is to present a therapeutic approach for TBI, taking into account the evidence supporting the role for oxidative stress in the pathophysiological processes of secondary brain injury. The role of agents such as mitochondria-targeted antioxidants (melatonin and new mitochondria-targeted antioxidants), nicotinamide adenine dinucleotide phosphate (NADPH) inhibitors (antioxidant vitamins and apocynin), and other compounds having mainly antioxidant properties (hydrogen-rich saline, sulforaphane, U-83836E, omega-3, and polyphenols) is covered. The rationale for innovative antioxidant therapies based on current knowledge and particularly the most recent studies regarding this field is discussed. Particular considerations and translational potential of new TBI treatments are examined and a novel therapeutic proposal for TBI is presented.