Background: Traumatic brain injury (TBI) initiates a neuroinflammatory cascade that contributes to neuronal damage and behavioral impairment. This study was undertaken to investigate the effects of wogonin, a flavonoid with potent antiinflammatory properties, on functional and histological outcomes, brain edema, and toll-like receptor 4 (TLR4)-and nuclear factor kappa B (NF-kB)-related signaling pathways in mice following TBI.Methodology/Principal Findings: Mice subjected to controlled cortical impact injury were injected with wogonin (20, 40, or 50 mg?kg 21 ) or vehicle 10 min after injury. Behavioral studies, histology analysis, and measurement of blood-brain barrier (BBB) permeability and brain water content were carried out to assess the effects of wogonin. Levels of TLR4/NF-kB-related inflammatory mediators were also examined. Treatment with 40 mg?kg 21 wogonin significantly improved functional recovery and reduced contusion volumes up to post-injury day 28. Wogonin also significantly reduced neuronal death, BBB permeability, and brain edema beginning at day 1. These changes were associated with a marked reduction in leukocyte infiltration, microglial activation, TLR4 expression, NF-kB translocation to nucleus and its DNA binding activity, matrix metalloproteinase-9 activity, and expression of inflammatory mediators, including interleukin-1b, interleukin-6, macrophage inflammatory protein-2, and cyclooxygenase-2.Conclusions/Significance: Our results show that post-injury wogonin treatment improved long-term functional and histological outcomes, reduced brain edema, and attenuated the TLR4/NF-kB-mediated inflammatory response in mouse TBI. The neuroprotective effects of wogonin may be related to modulation of the TLR4/NF-kB signaling pathway.