2‘-Hydroxycinnamaldehyde (HCA), a natural product isolated from the bark of Cinnamomum cassia, that has anti-inflammatory and anti-tumor activities. In this study, we explored whether HCA preconditioning could protect heart against ischemia/reperfusion (I/R) induced oxidative injury through cytosolic Bcl-2–associated athanogene 3 (BAG3) upregulation. In vivo HCA preconditioning was performed intraperitoneally 50 mg/kg body weight three times/week for 2 weeks before cardiac I/R injury in adult male Wistar rats. Animals were divided into sham control (SHAM), I/R and HCA preconditioning plus I/R (HCA+I/R) groups. We determined left ventricular pressure cardiac hemodynamics, microcirculation, electrocardiogram, infarct size, oxidative stress, western blot, immunohistochemistry and cytokine array assay. HCA pretreatment through BAG3 overexpression inhibited H2O2 induced H9c2 cell death. Cardiac I/R injury enhanced ST segment elevation, left ventricular end-diastolic pressure, infarct size, myocardial disruption, tissue edema, erythrocyte accumulation, leukocyte infiltration, reactive oxygen species, malondialdehyde, 8-isoprostane, caspase 3 mediated apoptosis, 4HNE/GPX4 mediated ferroptosis and fibrosis but decreased microcirculation, cytosolic BAG3 and Beclin-1/LC3 II mediated autophagy in the I/R hearts. HCA preconditioning significantly depressed these oxidative injury by increased cardiac cytosolic BAG3 and Nrf2/HO-1 signaling. HCA preconditioning significantly decreased cardiac I/R enhanced mitochondrial fission DRP1 expression. Our data suggest HCA preconditioning can efficiently improve myocardial I/R injury evoked cardiac dysfunction, apoptosis, ferroptosis and mitochondrial fission and autophagy inhibition through cardiac BAG3 and Nrf2/HO-1 upregulation.