OBJECTIVE: To investigate the therapeutic mechanism of Mai Guan Fu Kang Capsule (MGFKC) against coronary heart disease (CHD). METHODS: MGFKC constituents were identified by liquid chromatography-mass spectrometry (LC-MS). Network pharmacology predicted bioactive compounds, targets, and CHD-associated targets. Protein-protein interaction networks were constructed, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. A CHD animal model was used to assess myocardial histopathology, serum biomarkers, inflammatory cytokines, oxidative stress, PI3K/Akt signaling pathway protein expression, gut microbiota, and short-chain fatty acids (SCFAs) metabolism. KEY FINDINGS: Key active components included salvianolic acid B and luteolin. Network analysis indicated involvement of the PI3K/Akt signaling pathway. MGFKC alleviated myocardial injury and histopathological changes, suppressed inflammation and oxidative stress, and regulated PI3K/Akt protein expression. It also ameliorated gut microbiota dysbiosis and restored SCFAs metabolism. CONCLUSION: MGFKC exerts multi-target effects against CHD through synergistic regulation of the PI3K/Akt pathway, providing anti-inflammatory, antioxidant, and anti-apoptotic activities. Improvement of gut microbiota and SCFAs metabolism further contributes to its cardioprotective mechanism.