Trehalose has neuroprotective effects in neurodegenerative diseases. This study aimed to explore the impact of trehalose on traumatic brain injury (TBI) by investigating its role in neuroprotection. The TBI mice model was established utilizing the cortical impact technique followed by trehalose treatment. Traumatic neuronal injury induced by scratch followed by trehalose treatment was performed to mimic TBI in vitro. Memory function was assessed using the Water maze test. Brain damage was evaluated through various methods including brain water content analysis, Nissl staining, Evans blue exudation, and TUNEL staining. Biochemical and morphological changes related to ferroptosis post-TBI were also examined. The results showed that trehalose was found to enhance spatial memory, reduce brain injury, and inhibit ferroptosis in TBI mice, similar to ferroptosis inhibitors. The influence of trehalose on TBI was reversed by the SIRT3 inhibitor. Trehalose upregulated SIRT3 to increase SOD activity in TBI, which could also be counteracted by the SIRT3 inhibitor. Combining trehalose with a ferroptosis inhibitor had a more significant effect on reducing brain injury and inhibiting ferroptosis. Furthermore, in TBI mice treated with trehalose and SIRT3 inhibitors, the effect of trehalose was reversed by SIRT3 inhibitors, but the addition of ferroptosis inhibitors reversed the effect of SIRT3 inhibitors, as shown by decreased ferroptosis and neuronal apoptosis in damaged brain tissue. In summary, this study provides initial evidence that trehalose plays a crucial role in neuroprotection post-TBI through the SIRT3/SOD2 pathway-mediated ferroptosis.