Ethnopharmacological relevance: Musk (Moschus Moschiferus) is regarded as a key drug for treating brain injury-related nerve damage in both traditional Chinese medicine and Tibetan medicine. According to the theory of traditional Chinese medicine, musk has the characteristics of being pungent and warm, and acts on the heart and spleen meridians, with the effects of awakening the brain and opening the orifices, as well as promoting blood circulation and removing blood stasis. This makes it an important drug for treating acute brain injuries such as closed coma and stroke with phlegm obstruction. Modern research has revealed that musk has multiple neuroprotective mechanisms and anti-inflammatory/antioxidant effects. These findings support its therapeutic potential in targeting neuronal injury pathways in the prevention and treatment of HACE, and further translational research is warranted. Aim of the study: This study aimed to investigate the neuroprotective properties of musk and uncovering the mechanisms through which it may exert its beneficial effects against HACE. Materials and methods: The constituents of musk were analyzed using Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). Additionally, network pharmacology and proteomic profiling were applied to identify possible molecular targets and associated signaling pathways. In vivo experiments were carried out using a rat model simulating an altitude of 6000 m over a 48-h period, while in vitro investigations involved exposing cultured microglial cells to hypoxia for 6h. The effectiveness and mode of action of musk were evaluated using a range of experimental techniques, including brain water content analysis via brain water content (BWC), histopathological examination (HE), Enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), transmission electron microscopy (TEM), and flow cytometry (FCM). Results: The UPLC-MS analysis identified 117 active compounds within musk. The tumor necrosis factor (TNF) signaling pathway might play a central role in mediating the protective effects of musk through the network pharmacology and proteomics combination. Pharmacodynamic results showed that pretreatment with musk significantly improved HACE-related neurological deficits in rats, reduced brain swelling, and protected cerebral tissue structure. Moreover, musk substantially decreased levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1(3 (IL-1(3), and suppressed the expression of aquaporin-4 (AQP4) and hypoxia-inducible factor-1 alpha (HIF-1 alpha). TEM imaging and Western blot assays collectively confirmed that musk could counteract hypoxia-induced necroptosis in microglial cells. In vitro studies further revealed that musk preserved microglial cell viability, restrained inflammatory mediator release, and interrupted the TNF-alpha/RIPK1-mediated necroptotic pathway. Importantly, the administration of exogenous TNF-alpha partially diminished the protective effects of musk, supporting the conclusion that its mechanism involves the TNF-alpha/RIPK1 signaling cascade. Conclusions: Our findings indicate that musk alleviates HACE by suppressing necroptotic processes through modulation of the TNF-alpha/RIPK1 pathway. These results offer a promising therapeutic approach for managing high-altitude illnesses and provide important evidence for the scientific validation and clinical application of traditional herbal medicines.