Previous studies revealed that oxidative stress and inflammation are the main contributors to secondary injury after traumatic brain injury (TBI). In an earlier study, we reported that lutein/zeaxanthin isomers (L/Zi) exert antioxidative and anti-inflammatory effects by activating the nuclear factor-kappa B (NF-κB) and nuclear factor-erythroid 2-related factor 2 (Nrf2) pathways. However, its precise role and underlying mechanisms were largely unknown after TBI. This study was conducted to investigate the potential mechanism of L/Zi isomers in a TBI model induced by a cold injury model in mice. To investigate the effects of L/Zi, male C57BL/6j mice-induced brain injury using the cold trauma model was allocated into two groups (n = 7): (i) TBI + vehicle group and (ii) TBI + L/Zi group (20 mg/kg BW). Brain samples were collected 24 h later for analyses. L/Zi given immediately after the injury decreased infarct volume and blood–brain barrier (BBB) permeability; L/Zi treatment also significantly reduced proinflammatory cytokines, including interleukin1 beta (IL-1β), interleukin 6 (IL-6), and NF-κB levels and increased growth-associated protein 43 (GAP-43), neural cell adhesion molecule (NCAM), brain-derived neurotrophic factor (BDNF), and Nrf2 levels compared with vehicle control. These data suggest that L/Zi improves mitochondrial function in TBI models, possibly decreasing inflammation and activating the Nrf2 pathway.