SIRT1 knockdown downregulated the expressions of Nrf2, HO-1, and FTH1. Thus, our data demonstrated that fisetin attenuated DOX-induced cardiomyopathy associated with ferroptosis through the SIRT1/Nrf2/HO-1 pathway and the FTH1 axis. Here, SIRT1 is linked to cardiomyopathy.