BACKGROUND: Mitochondria play central role in cardiac energy metabolism modulations. Cardiac energy metabolism could be potential therapeutic target for the treatment of ischemic heart disease (IHD). We proposed strategy to analyze the regulation modes of astragaloside IV (AST) by targeting mitochondrial-energy-metabolism (MEM) in IHD based on transcriptome, network analysis, molecular docking (MD) and western blot (WB). METHOD: IHD-associated genes and AST potential targets were collected from databases and references. MEM-related genes were obtained from MitoProteome. Cytoscape was applied to construct networks, present visualization, and conduct KEGG pathway enrichment. AST regulated energy-metabolism-associated-IHD-network (AEIN) was created, and reverse rates calculated from network analysis of transcriptome from rat myocardial infarction experiments were assigned to AEIN. Binding affinities and modes were evaluated by MD with further WB validation of targets expression. RESULTS: The study identified 1713 IHD-related genes, 528 MEM-related genes, and 169 potential AST target genes. 21 AST targets were obtained from AEIN, while the top three targets Akt1, ERK1/2 and RPS6KB1 showed good binding affinities with AST (-10, -9.8, -8.6 and -8.8 kcal/mol for Akt1, Erk1, Erk2 and RPS6KB1 respectively). AST reversed the decreased expressions of three targets against OGD injury of H9c2. 13 MEM-associated signaling pathways, including HIF-1, and PI3K-Akt signaling pathways, were retrieved showing certain inter-relationships both in compositions and functions. CONCLUSIONS: AST may have coordinated roles among multi-pathways in regulating MEM homeostasis in IHD. While further deep investigations should be designed and conducted to decipher and pinpoint the multi-target, multi-pathway modes of action of AST in the future.