This study was designed to explore the anti heart failure mechanisms of the compatibility of Gualou with Xiebai based on network pharmacology in rat model of myocardial ischemia-reperfusion injury. Using the databases of Traditional Chinese Medicine Database@Taiwan (TCM Database@Taiwan), Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Drug Repositioning and Adverse Drug Reaction Chemical-Protein Interactome (DRAR-CPI) and Universal Protein Resource (Uniprot) to screen compounds and predict the target of active components, the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database, we predicted the biological pathway and signal pathway in the compatibility of Gualou with Xiebai. The effects of Gualou Xiebai dropping pills on the apoptosis of myocardial cells and the expression of protein kinase B (Akt), p-Akt and cysteine aspartate-specific proteinase (caspase-3) protein were examined in the related signal pathway phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) of myocardial ischemia reperfusion injury in rats. Twenty two compounds, such as 10 α-cucurbita-5, 24-diene-3β-ol and macrostemonoside were found to protect rats from heart failure through multiple targets, multiple biological pathways and multiple pathways, involving biological pathways such as hormone stimulation reaction, phosphorylation, apoptosis regulation, and signaling pathways such as insulin, mitogen-activated protein kinase (MAPK), cell apoptosis and so on. After the intervention of Gualou Xiebai dropping pills, the PI3K-Akt signaling pathway was activated to promote the phosphorylation of Akt protein, reduce the expression of caspase-3 protein, inhibit apoptosis and protect the myocardium. The data verify the results of the network pharmacology, and explain the mechanisms of anti-heart failure activity of combination of Gualou with Xiebai.