Doxorubicin (DOX) is an incessantly used chemotherapeutic drug that can cause detrimental dose-dependent effects such as cardiotoxicity and congestive heart failure. Studies have focused on therapeutic strategies such as exosomes derived from embryonic stem cell (ES-Exos) and antioxidants for example resveratrol; however, the function of mesenchymal stem cell-derived exosomes (MSC-Exos) have never been examined in DOX-induced pyroptosis. MSC-Exos maintains the therapeutic potential of exosome therapy without the ethical concerns. Hence, the current study focuses on determining whether MSC-Exos has the potential to ameliorate inflammation-induced cell death pyroptosis in our established in vitro DOX-induced cardiotoxicity (DIC) model. Rat embryonic cardiomyocytes (H9c2) were first exposed to DOX to stimulate pyroptosis, followed by subsequent treatment with MSC-Exos, with further analysis performed through immunocytochemistry, western blotting, and RT-PCR. We evaluated the therapeutic potential of MSC-Exos by investigating the pyroptotic initiator HMGB1 which binds to TLR4 resulting in the formation of the NLRP3 inflammasome that initiates pyroptosis by activating the pyroptotic markers, caspase-1, IL-1β and IL-18, and the pyroptotic executioner GSDMD. Our data depicted that treatment with MSC-Exos significantly (p