Heart failure (HF) is a complex and multifactorial disease responsible for over 17.3 million deaths annually, primarily mediated by oxidative stress-induced mitochondrial dysfunction. Artesunate (AS), an artemisinin derivative, possesses anti-inflammatory and antioxidative properties and is used to enhance mitochondrial function and reduce reactive oxygen species (ROS) generation. However, its specific effects and mechanisms in HF remain poorly understood. In this study, we investigated the impact of AS on Doxorubicin hydrochloride (Dox)-induced injury in H9C2 cardiomyocytes. The results showed that AS promoted cell viability, decreased ROS production and mitigated mitochondrial damage in Dox-exposed H9C2 cells. Importantly, AS also modulated the Silent information regulator 1 (SIRT1)/Forkhead box O3a (FOXO3a)/Manganese superoxide dismutase (MnSOD) pathway, indicating its potential therapeutic utility in HF by inhibiting ROS production and preserving mitochondrial function in doxorubicin-treated H9C2 cardiomyocytes.