Cortical and hippocampal neuronal damages caused by traumatic brain injury (TBI) are associated with motor and cognitive impairments; however, only little attention paid to the striatal damage. It is known that the p53 tumor-suppressor transcription factor participated in TBI-induced secondary brain damage. We investigated how the p53 inactivator pifithrin (PFT)-α affected TBI-induced striatal neuronal damage at 24 h post-injury. Sprague-Dawley rats subjected to a controlled cortical impact were used as TBI models. We observed that p53 mRNA significantly increased, whereas p53 protein expression was distributed predominantly in neurons but not in glia cells in striatum after TBI. PFT-α improved motor deficit following TBI. PFT-α suppressed TBI-induced striatal glial activation and expression of proinflammatory cytokines. PFT-α alleviated TBI-induced oxidative damage TBI induced autophagy was evidenced by increased protein expression of Beclin-1 and shift of microtubule-associated light chain (LC)3-I to LC3-II, and decreased p62. These effects were reduced by PFT-α. Post-injury PFT-α treatment reduced the number of degenerating (FJC-positive) and apoptotic neurons. Our results suggest that PFT-α may provide neuroprotective effects via p53-dependent or -independent mechanisms depending on the cell type and timing after the TBI and can possibly be developed into a novel therapy to ameliorate TBI-induced neuronal damage.