This study aimed to investigate the protective effect and potential mechanism of total flavonoids of Dracocephalum moldavica L. (TFDM) against doxorubicin (DOX)-induced cardiotoxicity (DIC) via the STING/NLRP3 signaling pathway. The protocol was approved by the Animal Ethics Committee of Xinjiang Institute of Materia Medica (approval No.: XJIMM-20250201). The DIC model was established by a single intraperitoneal injection of DOX (20 mg·kg^-1). Body weight, heart weight, heart index, and cardiac function (evaluated by echocardiography) were measured in each group. HE staining and Masson staining were used to observe myocardial tissue damage. Myocardial enzyme activities in serum, as well as oxidative stress indicators and inflammatory factor levels in myocardial tissue, were detected by corresponding kits. Western blot was performed to assess the expression of STING/NLRP3 pathway-related and pyroptosis key proteins in myocardial tissue. Additionally, the effects of TFDM (100 µg·mL^-1) on inflammatory factors and the STING/NLRP3 pathway in rat H9c2 cardiomyocytes stimulated by DOX or the STING agonist vadimezan (DMXAA) were further evaluated in vitro. In vivo experiments showed that TFDM effectively increased body weight, heart weight ratio, left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS), while decreasing left ventricular internal diameter at end-diastole (LVIDd) and left ventricular internal diameter at end-systole (LVIDs) in DIC mice. TFDM inhibited the abnormal elevation of myocardial enzymes, oxidative stress indicators and inflammatory factors, and ameliorated myocardial inflammatory infiltration and fibrosis. Furthermore, TFDM suppressed the activation of the STING/NLRP3 pathway and the expression of pyroptosis-related proteins in DIC mice. In vitro results demonstrated that TFDM intervention reduced the release of inflammatory factors; Western blot confirmed that both DOX and DMXAA significantly upregulated the expression of STING pathway and pyroptosis-related proteins, which were markedly downregulated after TFDM treatment. In conclusion, TFDM pretreatment exerts a protective effect against DIC by alleviating myocardial injury and improving cardiac function, and its mechanism may be associated with the inhibition of the STING/NLRP3 pathway to suppress cell pyroptosis and inflammatory cascade reaction.