Hepatitis C virus (HCV) infection may lead to hepatic insulin resistance (IR), and endoplasmic reticulum (ER) stress has been found to induce IR. In our previous study, naringenin (NGEN) had an insulin sensitization effect on the HCV core protein (HCVCP) infected mouse livers. In the present study, we examined the effects of NGEN on HCVCP infection-induced ER stress and investigated the insulin sensitization mechanism involved. We found that XBP1s was up-regulated in the livers of HCV-infected patients, in hepatocytes with HCV infection, and in HCVCP-infected mice. HCVCP induces ER stress in the mouse liver and hepatocytes by increasing XBP1s and downstream gene expression. Pre-treatment with NGEN inhibited the ER stress and downstream gene expression both in vivo and in vitro. Similar to the HCVCP infection results, NGEN also inhibited the ER stress in tunicamycin-treated Huh-7.5.1 cells. In addition, the role of IRE1α in HCVCP-induced IR was detected, and knockdown of IRE1α abolished HCVCP-stimulated IR. Overexpression induced IR but could be abolished by NGEN. NGEN also blocked the HCVCP-induced IRE1α expression levels that were up-regulated in vivo. Our data reveal that ER stress may be associated with HCV-induced IR, and NGEN treatment inhibited ER stress activity and increased insulin sensitivity by decreasing the expression of IRE1α.