Compound Longmaining (CLMN) decoction, a herbal formula from Traditional Chinese Medicine (TCM), has been widely used for the treatment of cardiovascular diseases, especially myocardial infarction (MI) in recent years. With limited knowledge of mechanisms underlying the therapeutic effect of CLMN on MI, this study was to use Network Pharmacology-based approach together with mice MI model to gain more insight of such mechanisms. The outcomes showed that 37 active compounds were identified constituting CLMN and targeting 444 genes, which were cross-referenced with MI associated genes, leading to identification of 24 target genes of CLMN for MI. Gene Ontology (GO) enrichment analysis of the 24 target genes was performed with 53 entries, amongst which include extracellular matrix decomposition, protein hydrolysis, cellular protein metabolism, protein hydrolysis, receptor binding, and NAD binding. There were 14 pathways generated using KEGG enrichment (p < 0.05). The constructed medicinal material-chemical component-target-pathway network identified seven core target with relatively higher values of degree and betweenness. in vivo experiments, where the effects of CLMN was examined on mice model of MI, confirmed that CLMN could protect myocardium by regulating these targets. The therapeutic effect of CLMN on MI is due to its effect in delaying ventricular remodeling, reducing myocardial fibrosis and apoptosis after MI, which can protect myocardial tissue.