ABSTRACT: Objective: This study employed network pharmacology to predict the active ingredients, molecular targets, and pathways underlying the cardiomyocyte proliferation effects of Suxiao Jiuxin Pill (SJP), followed by in vitro validation to elucidate its molecular mechanisms. Methods: Active compounds were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), with molecular targets retrieved from PubChem and SwissTargetPrediction. Cardiomyocyte proliferation-related targets were sourced from OMIM and GeneCards. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using Metascape. Experimental validation utilized HL-1 cardiomyocytes: CCK-8 assay determined optimal concentration and cell activity; HIF-1α levels and key signaling protein expression were assessed via Western blotting; cardiomyocyte proliferation post-hypoxia was examined using EdU assay; molecular docking of core proteins and key compounds was performed using AutoDock. Results:Thirty-nine bioactive SJP compounds (33 from Chuanxiong Rhizoma, 6 from Borneol) and 238 key drug-disease targets were identified in this study. GO enrichment revealed 359 molecular functions, and KEGG analysis identified 212 signaling pathways. CCK-8 assay indicated 10 μg/mL SJP exerted the strongest proliferative effect with an optimal hypoxia duration of 24 h. SJP treatment significantly increased the relative expression levels of p-PI3K, p-AKT, p-GSK3B, and β-catenin compared to the control group (P<0.05). Molecular docking demonstrated strong binding affinities of myricanone-MAPK3. Conclusion: Suxiao Jiuxin Pill promotes post-infarction myocardial repair by enhancing cardiomyocyte proliferation through the PI3K/AKT/GSK3β/β-catenin signaling pathway.