This study aimed to construct an ischemic cardiomyocyte-targeted and ROS-responsive drug release system to reduce myocardial ischemia-reperfusion injury (MI/RI). We constructed thioketal (TK) and cardiac homing peptide (CHP) dual-modified liposomes loaded with puerarin (PUE@TK/CHP-L), which were expected to deliver drugs precisely into ischemic cardiomyocytes and release drugs in response to the presence of high intracellular ROS levels. The advantages of PUE@TK/CHP-L were assessed by cellular pharmacodynamics, fluorescence imaging and animal pharmacodynamics. PUE@TK/CHP-L significantly inhibited apoptosis and ferroptosis in H/R-injured cardiomyocytes and also actively targeted ischemic myocardium. Based on these advantages, PUE@TK/CHP-L could significantly enhance the drug's ability to attenuate MI/RI. PUE@TK/CHP-L had potential clinical value in the precise treatment of MI/RI.