Background Anthracyclines, such as doxorubicin, and HER-2 blocking agents, like trastuzumab, are integral in breast cancer treatment but are associated with significant cardiotoxicity. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been suggested to provide cardio-renal benefits in the context of anthracycline therapy. However, the cardioprotective effects of SGLT2 inhibitors during combined anthracycline and HER-2 blocking agent therapy remain largely unexplored. Aims The study aimed to investigate the cardioprotective potential of Dapagliflozin in mitigating the cardiotoxic effects of anthracyclines and HER-2 blocking agents in preclinical models. Methods Preclinical models were utilized to assess the cardioprotective effects of Dapagliflozin in mouse treated with doxorubicin combined with HER-2 blocking agents. Cardiac function was evaluated through echocardiographic analysis, and myocardial tissue was examined for inflammatory markers including NLRP3, MyD-88, IL-1β, and IL-6 expression. Results Doxorubicin combined with HER-2 blocking agents led to significant reductions in cardiac function, evidenced by reduced ejection fraction and impaired radial/longitudinal strain. Additionally, a substantial increase in pro-inflammatory cytokines and NLRP3/MyD-88 inflammasome activation was observed. Dapagliflozin administration significantly mitigated these adverse effects by reducing myocardial expression of NLRP3, MyD-88, IL-1β, and IL-6, thereby improving cardiac function. Limitations While the study provides promising results in preclinical models, its translation into clinical settings is limited by the absence of human trials, and the long-term effects of Dapagliflozin in this context are yet to be fully understood. Conclusions This study presents the first evidence of Dapagliflozin’s cardioprotective and anti-inflammatory effects in the context of anthracycline and HER-2 blocking agent-induced cardiotoxicity. These findings support the potential use of Dapagliflozin for primary prevention of cardiovascular events associated with doxorubicin-trastuzumab therapy in breast cancer patients, warranting further clinical investigation