Pancreatic insulin-producing β-cell dysfunction and death plays central roles in the onset and progression of both type 1 and type 2 diabetes. Current antidiabetic drugs cannot halt the ongoing progression of β-cell dysfunction and death. In diabetes, a major cause for the decline in β-cell function and survival is endoplasmic reticulum (ER) stress. Here, we identified quinazoline derivatives as a novel class of β-cell protective agents against ER stress-induced dysfunction and death. A series of quinazoline derivatives were synthesized from dichloroquiazoline utilizing a sequence of nucleophilic reactions. Through SAR optimization, 2,4-diaminoquinazoline compound 9c markedly protects β-cells against ER stress-induced dysfunction and death with 80% maximum rescue activity and an EC50 value of 0.56 μM. Importantly, 9c restores the ER stress-impaired glucose-stimulated insulin secretion response and survival in primary human islet β-cells. We showed that 9c protects β-cells by alleviating ER stress through the suppression of the induction of key genes of the unfolded protein response and apoptosis.