Ischemia/reperfusion (I/R) injury is an inevitable process during heart transplant and suppressing I/R injury could greatly improve the survival rate of recipients. Mesenchymal stem cells (MSCs) have positive effects on I/R. We aimed to investigate the mechanisms underlying the protective roles of MSCs in I/R. Both cell model and rat model of myocardial I/R were used. MTT assay and flow cytometry were used to measure cell viability and apoptosis, respectively. QRT-PCR and western blotting were employed to measure levels of lncRNA HCP5 (HLA complex P5), miR-497, apoptosis-related proteins, and insulin-like growth factor (IGF1)/PI3K/AKT pathway. Dual luciferase assay was used to validate interactions of HCP5 and miR-497, miR-497 and IGF1. Echocardiography was performed to evaluate cardiac function of rats. Serum levels of CK-MB and LDH were measured. H&E and Masson staining were used to examine morphology of myocardial tissues. hBMSC-derived exosomes (hBMSC-Exos) increased the viability of cardiomyocytes following hypoxia/reperfusion (H/R) and decreased apoptosis. H/R diminished HCP5 expression in cardiomyocytes while hBMSC-Exos recovered the level. Overexpression of HCP5 in hBMSC-Exos further enhanced the protective effects in H/R while HCP5 knockdown suppressed. HCP5 directly bound miR-497 and miR-497 targeted IGF1. miR-497 mimics or si-IGF1 blocked the effects of HCP5 overexpression. Further, hBMSC-Exos alleviated I/R injury in vivo and knockdown of HCP5 in hBMSC-Exos decreased the beneficial effects. AntagomiR-497 blocked the effects of HCP5 knockdown. HCP5 from hBMSC-Exos protects cardiomyocytes against I/R injury via sponging miR-497 to disinhibit IGF1/PI3K/AKT pathway. These results shed light on mechanisms underlying the protective role of hBMSC-Exos in I/R.