BACKGROUND Hepatic ischaemia-reperfusion injury (HIRI) is an unavoidable process in liver transplantation, where apoptosis plays a critical role. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-exos), which constitute a cell-free therapeutic approach, have garnered extensive attention in alleviating HIRI. However, the potential of hucMSC-exos in mitigating apoptosis and their underlying mechanisms remain largely unknown.AIM To investigate the effects of hucMSC-exos on apoptosis after HIRI and explore the underlying mechanisms. METHODS The therapeutic effects of hucMSC-exos on HIRI and hypoxia/reoxygenation injury in L02 cells were investigated. RNA sequencing was used to detect differentially expressed genes in L02 cells after hucMSC-exo treatment, and the expression of apoptosis markers in L02 cells was analyzed. MicroRNA (miRNA) sequencing was performed to analyse the miRNA expression profiles of hucMSC-exos and L02 cells after hucMSC-exo treatment. Through a miRNA-mRNA integrated analysis, candidate miRNAs and their regulated target genes were identified. We subsequently studied the roles of these candidate miRNAs in mouse HIRI and L02 cell hypoxia/reoxygenation injury. RESULTS Fluorescence confocal microscopy revealed that hucMSC-exos effectively homed to the liver and were taken up by hepatocytes, likely due to the presence of anti-very late antigen-4 and anti-lymphocyte function-associated antigen-1 on the surface of hucMSC-exos. HucMSC-exos alleviate hepatocyte damage by inhibiting apoptosis. Specifically, let-7i-5p within hucMSC-exos inhibited the expression of the factor-related apoptosis ligand protein in L02 cells, leading to the upregulation of B-cell lymphoma-2 and the downregulation of B-cell lymphoma-2-associated X protein and cysteinyl aspartate specific proteinase-3, thereby inhibiting L02 cell apoptosis and enhancing cell proliferation activity. The overexpression of let-7i-5p effectively enhanced the antiapoptotic effects of hucMSC-exos both in vitro and in vivo. CONCLUSION Our findings indicate that hucMSC-exos alleviate HIRI by inhibiting apoptosis. We demonstrated that hucMSC-exos target apoptosis in L02 cells and mediate the let-7i-5p/factor-related apoptosis ligand pathway, thereby ameliorating HIRI. This study provides new insights into the role of hucMSC-exos in hepatocyte apoptosis and highlights the potential of hucMSC-exos as a therapeutic strategy for HIRI.