Mitochondrial dysfunction is a critical driver of cardiac remodeling under conditions of chronic stress, such as hypertension and heart failure. Andrographolide, a bioactive diterpenoid from Andrographis paniculata, has demonstrated antioxidative and anti-inflammatory effects; however, its role in mitochondrial quality control within the heart remains unclear. In this study, a network pharmacology approach was applied to explore the molecular targets of andrographolide related to mitochondrial dysfunction in cardiac remodeling. A total of 1763 mitochondrial-associated cardiac remodeling genes were retrieved from CardGenes and intersected with 539 andrographolide-related targets identified using PharmMapper, SwissTargetPrediction, and the comparative toxicogenomics database (CTD). Fifty-four overlapping genes were subjected to protein–protein interaction analysis using STRING and Cytoscape. The top-ranked hub gene was identified as TP53. Functional enrichment indicated key involvement in the PI3K-Akt, mitogen-activated protein kinases (MAPK), Forkhead box protein (FOXO), and AGE-RAGE pathways, linking andrographolide to the modulation of oxidative stress, metabolism, and cell survival. Gene ontology (GO) terms supported roles in kinase activity and membrane-associated signaling. Molecular docking showed strong binding affinities between andrographolide and TP53 regulators, particularly ataxia telangiectasia mutated (ATM) (−8.63 kcal/mol, Kd 6.34 × 10−7 M) and checkpoint 2 (CHK2) (−8.47 kcal/mol, Kd 4.68 × 10−7 M). Machine learning predictions indicated favorable LELP and moderate bioactivity for ataxia telangiectasia Rad3-related (ATR), CHK2, and Sirtuin 1 (SIRT1). These findings suggest that andrographolide exerts cardioprotective effects by modulating mitochondrial stress signaling and p53 regulatory networks. Further experimental validation is warranted to confirm its therapeutic potential in cardiac remodeling-related diseases. © 2025 Fadhillah et al.