The present study aimed to explore the holistic mechanism for the antihypertrophic effect of a compound in Chinese medicine, QiShenYiQi Pills (QSYQ) and the contributions of its components to the effect in rats with cardiac hypertrophy (CH). After induction of CH by ascending aortic stenosis, rats were treated with QSYQ, each identified active ingredient (astragaloside IV, 3, 4-dihydroxy-phenyl lactic acid or notoginsenoside R1) from its 3 major herb components or dalbergia odorifera, either alone or combinations, for 1 month. QSYQ markedly attenuated CH, as evidenced by echocardiography, morphology and biochemistry. Proteomic analysis and western blot showed that the majority of differentially expressed proteins in the heart of QSYQ-treated rats were associated with energy metabolism or oxidative stress. Each ingredient alone or their combinations exhibited similar effects as QSYQ but to a lesser extent and differently with astragaloside IV and notoginsenoside R1 being more effective for enhancing energy metabolism, 3, 4-dihydroxy-phenyl lactic acid more effective for counteracting oxidative stress while dalbergia odorifera having little effect on the variables evaluated. In conclusion, QSYQ exerts a more potent antihypertrophic effect than any of its ingredients or their combinations, due to the interaction of its active components through a multi-component and multi-target mode.