Chronic exposure to high altitudes causes pathophysiological cardiac changes that are characterized by cardiac dysfunction, cardiac hypertrophy, and decreased energy reserves. However, finding specific pharmacological interventions for these pathophysiological changes is challenging. In this study, we identified tetramethylpyrazine (TMP) as a promising drug candidate for cardiac dysfunction caused by simulated high-altitude exposure. By utilizing hypobaric chambers to simulate high-altitude environments, we found that TMP improved cardiac function, alleviated cardiac hypertrophy, and reduced myocardial injury in hypobaric hypoxic mice. RNA sequencing showed that TMP also upregulated heart-contraction-related genes that were suppressed by hypobaric hypoxia exposure. Mechanistically, TMP inhibited hypobaric hypoxia-induced cardiac Ca²⁺/calmodulin-dependent kinase II (CaMKII) activation and exerted cardioprotective effects by inhibiting CaMKII. Our data suggest that TMP application may be a promising approach for treating high-altitude-induced cardiac dysfunction, and they highlight the crucial role of CaMKII in hypobaric hypoxia-induced cardiac pathophysiology.