ETHNOPHARMACOLOGICAL RELEVANCE: Guanxin II, proposed by Chen Keji (National master of traditional Chinese medicine), possesses neuroprotective effect. Interestingly, its simplified prescription Danshen-Chuanxiong-Honghua (DCH) can also clinically ameliorate cerebral impairment and improve spatial cognitive deficits, similar to the function of original formula. AIM OF THE STUDY: We aimed to elucidate the rationality of DCH's natural existence, qualitatively identify DCH-derived phytochemicals, thereby to validate cerebral protective effect, and expose the potential mechanism of DCH and its main absorbed compound ferulic acid (FA). MATERIALS AND METHODS: The natural rationality of DCH's existence for treating TBI was verified using data mining. The qualitative analysis of DCH extract-derived phytochemicals was conducted through liquid chromatography with mass spectrometry (LC-MS). Controlled cortical impact (CCI) was chosen to establish TBI model. Neurological behavior tests, blood-brain barrier (BBB) permeability test, brain water content measurement, and proinflammatory factors consisting of IL-6, IL-1β, and TNF-α of plasma, and HPA axis-related hormone levels of DA, NA, 5-HT, ghrelin, and BDNF in hippocampus were analyzed by enzyme-linked immunosorbent assay. Network pharmacology was employed to predict potential targets and pathways of DCH intervening TBI. Growth hormone secretagogue receptor (GHSR) antagonist [D-Lys3]-GHRP-6 (D-Lys3) was injected intraperitoneally in TBI rats after waking up. Molecular docking and pharmacological experiment with D-Lys3 were used to verify the pathway. RESULTS: Twenty-six phytochemicals were identified based on LC-MS. FA, as the primary contributor of DCH, alleviated disruption of BBB and reduced brain edema, suppressed the secretion of proinflammatory factors, such as IL-6, IL-1β, TNF-α, as well as HPA axis-related hormones such as DA, NA, and 5-HT, and ghrelin, and BDNF by regulating the Ghrelin/GHSR pathway. These results were validated by GHSR receptor antagonist, as well as molecule docking. CONCLUSIONS: Taken together, DCH, when prescribed for the treatment of TBI, has a certain degree of reasonableness. FA, as the main absorbed component, demonstrated a similar function to DCH in improving the blood-brain barrier, promoting neural recovery, and anti-inflammatory effects in TBI rats, primarily via modulating Ghrelin/GHSR.