Background <p>Atrial Fibrillation (AF) is the most common arrhythmia in clinical practice, and age is an independent risk factor for the development of AF. Qi-Po-Sheng-Mai granule (QPSM) has been used clinically to treat aging-related AF, however, its underlying mechanisms remain incompletely understood.</p> Methods <p>In this study, we established a D-galactose-induced aging rat model to evaluate the effects of QPSM on aging-related AF through electrocardiograms, echocardiography, and histopathological analysis. Further, we employed transcriptomics and metabolomics to uncover molecular mechanisms and targets. Finally, in vivo experiments were conducted to validate the expression of key targets in the D-Gal-induced aging rat model and the intervention effects of QPSM.</p> Results <p>QPSM significantly reduced the susceptibility to AF in aging rats and alleviated atrial dilation and fibrosis. The combined analysis of transcriptomics and metabolomics suggested that QPSM may inhibit the occurrence of aging-related AF by modulating Nampt expression and increasing NAD⁺ content in atrial tissue. Additionally, in vivo experiments confirmed that QPSM increased ATP content, reduced mitoSOX fluorescence intensity, and decreased the proportion of senescent cells. Whole-cell patch clamp results showed that QPSM could prolong the action potential duration of isolated atrial cells, increase <i>I</i>_caL. This might be achieved by regulating the expression of Oxi-CaMKII and RyR₂^ser2814, thereby alleviating calcium overload in atrial cells.</p> Conclusions <p>Our study demonstrates that QPSM may reduce the susceptibility to aging-related AF by regulating Nampt expression and NAD⁺ content, thereby mitigating calcium overload in atrial cells. This provides a direction for future research in related fields.</p> Graphical Abstract <p></p>