Background: During rapid ascent to high altitudes, myocardial tissue is highly susceptible to injury. Consequently, preventing acute hypobaric hypoxia-induced myocardial injury (AHMI) is critical. Muscone, which is widely used in cardiovascular therapeutics, shows potential in mitigating AHMI, but its efficacy and mechanisms require further investigation. Purpose: This study investigates the efficacy and molecular mechanisms of muscone intervention in AHMI. Methods: Following pretreatment with muscone, a hypobaric hypoxic chamber was used to develop a rat model of heart injury. Myocardial injury severity was assessed via electrocardiography (ECG), hematoxylin-eosin (H&E) staining, and serum biochemical markers. Oxidative stress and apoptosis-related indicators were evaluated using flow cytometry, transmission electron microscopy, western blotting, and TUNEL staining. Transcriptomics, molecular docking, cellular thermal shift assay (CETSA), and immunofluorescence were employed to identify signaling pathways and key targets underlying muscone's intervention in AHMI. Further mechanistic validation was conducted using H9c2 cells subjected to hypobaric hypoxia. Both pharmacological inhibition (EX-527) and genetic knockdown (siRNA) of SIRT1 were employed to confirm the functional necessity of SIRT1 in muscone's action. Results: Pretreatment with muscone significantly attenuated hypobaric hypoxia-induced myocardial injury in rats, ameliorating cardiac conduction abnormalities, reducing serum levels of injury markers (cardiac troponin T [cTnT], creatine kinase-MB [CK-MB], lactate dehydrogenase [LDH]), and improving myocardial histopathology. Concurrently, it elevated activities of antioxidant enzymes (catalase [CAT], glutathione peroxidase [GSH-Px], superoxide dismutase [SOD]) while decreasing malondialdehyde (MDA) content. Ultrastructural analysis confirmed protection against subcellular damage and suppression of cardiomyocyte apoptosis. Mechanistically, transcriptomics implicated SIRT1-mediated FOXO pathway regulation. Molecular docking and CETSA supported potential binding between muscone and SIRT1, while western blot (WB) and immunofluorescence revealed upregulated myocardial SIRT1 expression. In vitro, muscone induced SIRT1-mediated deacetylation of FOXO3a, which reduced its nuclear translocation and transcriptionally repressed the pro-apoptotic Bim. These effects suppressed oxidative stress and apoptosis. Importantly, both the SIRT1 inhibitor EX-527 and SIRT1-specific siRNA abolished the protective effects of muscone, confirming the essential and indispensable role of the SIRT1/ FOXO3a pathway. Conclusions: This study demonstrated that muscone ameliorated AHMI. Mechanistically, muscone attenuated myocardial damage by suppressing oxidative stress and cardiomyocyte apoptosis. These benefits were likely mediated via the SIRT1/FOXO3a pathway, suggesting SIRT1 as a promising target for muscone in AHMI treatment.