Hypoxia-induced damage is one of the key factors associated with islet graft dysfunction. And NLRPS played an important roles in cell death due to hypoxia. In prior study, we found that human mesenchymal stem cell-derived exosomes could protect neonatal porcine islet cell clusters (NICCs) from hypoxia induced dysfunction. Here, we investigated whether human mesenchymal stem cell-derived exosomes could effect the survival and function of anoxic NICCs via NLRP3 inflammasome pathway. The NICCs were cultured with or without human mesenchymal stem cell-derived exosomes(control group) under 20% O2 or 1% O2 conditions for 3 days. The viability and function of NICCs in different group were studied by fluorescence activated cell sorter (FACS) and the extra-cellular flux assay, respectively. The expression of hypoxia survival and NLRP3 inflammasome activation related proteins was detected by Western-blot. Tubing loops model and TUNEL assay were performed to confirm the apoptosis-resistant ability of NICC in different groups. Compared with the control groups, the results showed that the survival ratio, viability, and function were improved significantly in NICCs cultured with exosomes (P<0.05). The expression of hypoxia-inducible factor 1α（HIF-1α）was up-regulated, meanwhile, the expression of NLRP3 inflammasome pathway and apoptosis associated proteins decreased in Western-blot assay. Our results demonstrate that human mesenchymal stem cell-derived exosomes can protect NICCs from hypoxia-induced dysfunction by suppression of inflammation via regulation in reactive oxygen species (ROS)-NLRP3-the thioredoxin-interacting protein(TXNIP) axis, which was characterized by pretreating with the ROS scavenger N-acetylcysteine (NAC) and performing TXNIP knockdown. It provides new insight into the relationship between mesenchymal stem cell-derived exosomes and hypoxia induce inflammation in islet transplantation.