<p>Doxorubicin (DOX) is limited in clinical application because of its cardiotoxicity. One of the key elements of DOX-induced cardiotoxicity is pyroptosis, a kind of programmed cell death brought on by immunity and followed by inflammatory response. Growth differentiation factor (GDF) 11 plays an significant role in oxidative stress and inflammation. The purpose of this work was to determine if GDF11 inhibits oxidative stress and pyroptosis in order to lessen the cardiotoxicity caused by DOX. SD rats were used to establish an in vivo model by intraperitoneal injection of DOX and induction of GDF11 overexpression in the heart using adeno-associated virus type 9 (AAV9). Human cardiomyocytes (AC16) were used to create the <i>in-vitro</i> model. By measuring the degree of cardiac function, cardiac fibrosis, inflammation, and oxidative stress; using transmission electron microscopy to examine the rat heart's microstructure; analyzing the expression of proteins of pyroptosis and oxidative stress-associated nuclear factor E2-related factor (Nrf-2)/heme oxygenase-1 (HO-1) pathway, the protective mechanism of GDF11 against DOX-induced cardiotoxicity was explored. GDF11 decreased the expression level of cardiac function, oxidative stress and inflammation-related indexes, attenuated the degree of DOX-induced cardiac fibrosis, and had some protective effects against damage to the rat heart's microstructures. Besides, GDF11 decreased the level of oxidative stress and restored the levels of anti-oxidative stress and other proteins, including Nrf-2, while also reduced the expression of DOX-induced pyroptosis-related proteins. GDF11 attenuates DOX-induced cardiotoxicity by inhibiting pyroptosis and oxidative stress, which provides new ideas for clinical improvement of DOX-induced myocardial injury.</p> Graphical abstract <p></p>