ER stress is an early event of acute kidney injury and has been linked to accelerate the development of chronic kidney disease. Therefore, the compounds that can mimic ER stress inhibitor may confer regulatory effects on ER stress induced apoptosis. In this study, we investigated the protective effects of flavonoid morin against ER stress induced apoptosis in human renal proximal tubular HK-2 cells. Morin downregulated the expression of GRP78, central regulator of ER stress response, induced by ER stress inducer tunicamycin. Interestingly, morin selectively inhibited the IRE1 pathway among the three major arms of the ER stress responses. The increased expression of XBP1-sp, phosphor-IRE-1α, and phosphor-JNK by TM were markedly suppressed by the pretreatment of morin. Morin also decreased the intracellular ROS production and the apoptosis induced by TM in HK-2 cells. Taken together, our finding show that morin acts as an ER stress inhibitor, and can be a good candidate in various ER-stress associated kidney diseases.