Neurological dysfunction is a common complication of traumatic brain injury (TBI), and early treatments are critical for the long-term prognosis. This study aimed to investigate whether hypidone hydrochloride (YL-0919) improves neurological function impairment in mice with TBI.TBI was induced in adult male C57BL/6J mice using the controlled cortical impact (CCI) method. First, the modified neurological severity score (mNSS), rotarod test, and Morris water maze (MWM) test were conducted to assess the impact of YL-0919 on neurological function in mice with TBI. Next, immunofluorescence and laser speckle contrast imaging were utilized to measure the number and activation of microglia and cerebral blood flow (CBF) after TBI. Enzyme-linked immunosorbent assays (ELISAs) were employed to assess the inflammatory factors. Finally, Western blotting was performed to measure the expression of proteins. Golgi-Cox staining was utilized to investigate the structure of pyramidal neurons.YL-0919 significantly alleviated neurological dysfunction in TBI+YL-0919 mice compared with TBI+Vehicle mice, increased the time spent on the rotarod (F = 1.297, P <0.05), and partially relieved cognitive dysfunction in TBI mice (for mNSS, F = 5.540, P <0.01; for MWM test, F = 30.78, P <0.05). Additionally, YL-0919 effectively inhibited the proliferation and activation of microglia (both P <0.01), promoted the recovery of CBF around the brain injury site and inhibited the expression of tumor necrosis factor-α (F = 9.142, P <0.05) and IL-1β (F = 4.662, P <0.05), and increased the concentration of IL-4 (F = 5.172, P <0.05). Furthermore, continuous gavage of YL-0919 (2.5 mg/kg) for seven days effectively increased the protein expression of brain-derived neurotrophic factor (BDNF), promoted the phosphorylation of mammalian target of rapamycin (mTOR), increased postsynaptic density protein 95 (PSD95) and synapsin1 levels, and increased the neuronal dendritic complexity and the dendritic spine density around the brain injury site (all P <0.05).Our findings indicated that YL-0919 can ameliorate neurological dysfunction in mice after TBI through the suppression of inflammation and the stimulation of the BDNF-mTOR signaling pathway. These findings provide an insightful perspective on the potential pharmacological mechanism involved in the neuroprotective effect of YL-0919.Copyright © 2025 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.