Background: Aging is a major factor for cardiovascular disease, and cardiac aging is closely related to the incidence of cardiovascular disease. Clarifying the mechanism of cardiac aging and finding reliable intervention is critical for preventing cardiovascular diseases and achieving healthy longevity. Traditional Chinese medicine Yiqi Huoxue Yangyin (YHY) decoction has unique advantage in the treatment of cardiovascular disease and aging. However, the associated molecular mechanisms remain unknown.Purpose: The present study aimed to verify the efficacy of YHY decoction against cardiac aging in D-gal-induced mouse model, and explore the potential mechanism of YHY decoction treatment through whole-transcriptome sequencing technique, providing novel insights into the molecular basis of YHY decoction in treating cardiac aging.Methods: The component of YHY decoction was identified by High Performance Liquid Chromatography (HPLC). D-gal-induced aging mouse model was established for this study. HE and Masson staining were applied to determine pathological changes of heart; telomere length, telomerase activity, AGEs and p53 were used to evaluate the degree of heart aging. Transcriptome sequencing, GO, KEGG, GSEA and ceRNA network were applied to analyze the potential mechanism of YHY decoction treatment of cardiac aging.Results: In this study, we found that YHY decoction not only improved the pathological structure of aging heart, but also regulated the expression of aging-related markers, telomere length, telomerase activity, AGEs and p53, the myocardial tissue, suggesting that it has a specific effect in delaying cardiac aging. Whole-transcriptome sequencing showed that the total of 433 mRNAs, 284 lncRNAs, 62 miRNAs, and 39 circRNAs were significantly differentially expressed after YHY decoction treatment. According to the analysis results of KEGG and GSEA, the differentially expressed mRNAs were found significantly involved in immune system, cytokine-cytokine receptor interaction and cell adhesion molecules. The ceRNA network showed that miR-770, miR-324, and miR-365 are localized in center, mainly affecting the immune system, PI3K-Akt signaling pathway, and MAPK signaling pathway.Conclusion: In conclusion, our results evaluated the ceRNA network of YHY decoction in treating cardiac aging for the first time, which could provide better understanding of the potential mechanism of YHY decoction treatment of cardiac aging.