<p>Astragaloside IV (AS-IV), a bioactive compound renowned for its anti-inflammatory, antioxidant, and anti-apoptotic properties, has not yet been investigated for its potential role in modulating cardiac function under high-altitude conditions. This study elucidates the cardioprotective effects of AS-IV against high-altitude-induced cardiac injury and explores the underlying molecular mechanisms. Under hypobaric hypoxia, we observed significant cardiac dysfunction, hypertrophy, and fibrosis, as confirmed by comprehensive echocardiographic, histopathological, and molecular analyses. Remarkably, AS-IV administration effectively attenuated these pathological changes, restoring cardiac architecture and function while mitigating oxidative stress and apoptosis. Further in vivo and in vitro experiments revealed that AS-IV preserves mitochondrial integrity by enhancing membrane potential, ameliorating mitochondrial impairment, and modulating calcium homeostasis through the calcium-sensing receptor (CaSR)-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling axis. Network pharmacology-based screening identified key molecular targets, including epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and mouse double minute 2 (MDM2), which were subsequently validated via molecular docking studies demonstrating strong binding affinities between AS-IV and these core proteins. Mechanistic investigations further revealed that siRNA-mediated EGFR knockdown or pharmacological activation of CaSR abolished AS-IV’s cardioprotective effects, including its anti-apoptotic, antioxidant, and mitochondrial-stabilizing properties. Taken together, our findings demonstrate that AS-IV exerts its therapeutic effects through a dual-pathway mechanism involving (1) the EGFR-PI3K-AKT-MDM2 axis and (2) CaSR-NF-κB signaling. These insights position AS-IV as a promising candidate for the prevention and treatment of high-altitude-related cardiovascular diseases.</p>