Gentianella acuta (GA) is a folk medicine used by Ewenki people in Inner Mongolia to treat heart disease. Transcriptional inhibition caused by the increase of DNMT1/3A/3B levels inhibited Nrf2, an anti-aging factor with antioxidant effect in aging myocardia, and the level of Nrf2 decreased with the increase of age. The main chemical component of GA, xanthones, can reverse this inhibition. In this study, D-gal was injected subcutaneously to establish an aging mouse model, and echocardiography was helpful to evaluate myocardial damage. Myocardial histological changes were detected by haematoxylin eosin and Masson's trichrome staining. The activities of catalase (CAT) and total superoxide dismutase (T-SOD) and the content of malondialdehyde (MDA) in serum of mice were detected to investigate the relationship between GA and oxidative stress. The serum levels of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were determined to investigate the effects of GA on aging mice. Results showed that Xanthones could alleviate myocardial damage and fibrosis, significantly improve diastolic dysfunction, gradually decrease MDA content, gradually increase T-SOD and CAT activities, and decrease serum TNF-α, IL-6 and IL-1β contents in aging mice. Reduce cardiac structural disorders, reduce inflammatory infiltration. In addition, GA reduces inflammation by promoting Nrf2 expression, inhibiting DNMT1/3A/3B levels, and activating the p53/p21 signaling pathway. This study suggests that GA has a protective effect on D-gal-induced cardiac aging, which may be related to the activation of p53/p21 signaling pathway and epigenetic regulation of Nrf2 level.