Ferroptosis is a newly identified and novel form of cell death, which is characterized by an iron- and reactive oxygen species (ROS)-dependent manner. Potential utility of ferroptotic cell death has been recently proposed for cancer treatment. Meanwhile, ROS generation and apoptosis are inherently consequent to cell apoptosis and dysfunction during islet cell preparation and transplantation. Whether ferroptosis induction is a regulator for cell viability and function in human pancreatic islet-cell clusters (ICCs) derived from pancreatic progenitor cells (PPCs) remains elusive. We thus sought to induce ferroptosis in our established cell culture system of human PPCs/ICCs, examine the effects of ferroptosis on ICCs, and explore the potential regulatory pathways involved. Our results showed that ICCs were prone to the use of ferroptosis-inducing and inhibiting agents under our culture conditions. Erastin, a ferroptosis inducer, was found to trigger ferroptosis in ICCs, without the apparent detection of other types of cell death involved, such as apoptosis and autophagy. In corroboration, the use of ferroptosis inhibitor, ferrostatin-1 (Fer-1), was found to enhance the cell viability of ICCs and prevent them from ferroptosis as well as improve its function. Mechanistically, the erastin-induced ferroptosis in ICCs was probably mediated via activation of JNK/P38/MAPK pathways and upregulation of NOX4 expression. Together, our findings may provide a scientific basis of ferroptosis inhibition as a potential for the amelioration of ICC survival and functionality during islet transplantation in diabetic patients.