Background: Acute myocardial infarction (AMI) is a major cardiovascular disease. Exosomes from mesenchymal stem cells (MSCs) are known to ameliorate myocardial ischemia-reperfusion (I/R) injury, and aberrant expression of UbiA prenyltransferase domain-containing protein 1 (UBIAD1) is linked to cardiovascular pathologies. However, it remains unclear whether MSC-derived exosomes mediate myocardial I/R injury by regulating UBIAD1. Methods: MSCs were identified by flow cytometry and differentiation assays (Alizarin Red and Oil Red O). Exosomes were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), western blot, and immunofluorescence. Differentially expressed genes were analyzed using bioinformatics analysis. An in vitro H/R damage model was established. Protein expression was examined by western blot. For function, the cell viability, lactate dehydrogenase (LDH), malonaldehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) levels were detected using corresponding assay kits. Cell apoptosis was examined using flow cytometry. Cross-analysis of the transcription factors predicting UBIAD1 in hTFtarget with highly expressed genes in GSE202991 was analyzed using a Venn diagram. Besides, the interaction between ZEB1 and UBIAD1 was predicted and verified via JASPAR database, chromatin immunoprecipitation assay (ChIP) and dual-luciferase reporter assays. Results: Up-regulated UBIAD1 mitigated H/R-induced injury in AC16 cells. Conversely, silencing UBIAD1 abrogated MSC-Exo-induced action of mitigation on H/R-induced AC16 cell injury. ZEB1 could bond to UBIAD1. Moreover, exosomes derived from sh-ZEB1-transfected MSCs reduced H/R-induced apoptosis and oxidative stress in cardiomyocytes. Importantly, exosomal ZEB1 alleviated H/R‑induced apoptosis, oxidative stress, and endoplasmic reticulum stress (ERS) through increasing UBIAD1. Conclusion: MSC-derived exosomal ZEB1 remits H/R-stimulated cardiomyocyte apoptosis, oxidative stress, and ERS via regulating UBIAD1.