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Traumatic brain injury (TBI) is a leading cause of death and disability. Secondary injuries that develop after the initial trauma contribute to long-lasting neurophysiological deficits. Polarization of microglia/macrophages toward a pro-inflammatory (M1) phenotype may increase the progression of secondary injury following TBI; however, the regulatory and functional mechanisms underlying these changes remain poorly defined. In the present study, we showed elevated expression of NADPH oxidase 2 (NOX2) and activation of nuclear factor-kappa B (NF-κB) predominantly in microglia/macrophages at 4- and 7-days after controlled cortical impact in mice. Delayed inhibition of NOX2, beginning one day after TBI, reduced reactive oxygen species production of myeloid cells and protected neurons from oxidative damage. Moreover, delayed NOX inhibition or global genetic NOX2 knockout suppressed the M1 “pro-inflammatory” profile of microglia/macrophages and simultaneously increased the M2 “anti-inflammatory” profile in the injured brain. These changes were associated with marked down-regulation of the classical NF-κB pathway in microglia/macrophages and reduced production of pro-inflammatory cytokines, tumor necrosis factor-α and interleukin-1β, after TBI. Finally, we demonstrated that wild-type microglia/macrophages isolated from the ipsilateral cortex at 7 days post-TBI were neurotoxic to co-cultured primary neurons, whereas this neurotoxicity was largely attenuated in microglia/macrophages from NOX2-KO mice. Taken together, our study shows a direct link between NOX2 and the NF-κB pathway in microglia/macrophages after TBI, and it provides a novel mechanism by which NOX2 activation leads to the enhanced inflammatory response and neuronal damage after brain injury. Our data also supports the therapeutic potential of targeting NOX2, which may provide efficacy with an extended therapeutic window after TBI.NOX2 and the classical NF-κB pathway are activated in microglia/macrophages at 4- and 7-days after TBI.NOX2-induced oxidative stress is directly linked to the neuroinflammatory and neurotoxic responses after TBI.A mechanism by which NOX2 regulates the polarization of microglia/macrophages through the NF-κB pathway is proposed.