Impaired insulin sensitivity of insulin-sensitive tissues plays a major role in the pathogenesis of type 2 diabetes, salvianolic acid B (SalB), a natural antioxidant usually treated various cardiovascular diseases was also reported potential utility on diabetes and dyslipidemia. Based on these, we aimed to explored whether the antioxidant effect of SalB play a pivotal role in the molecular mechanisms leading to insulin resistance. We found that SalB improved glucose tolerance and insulin sensitivity, decreased serum ALT, AST and ALP levels of ob/ob mice. Also, transcription of Bip and CHOP, phosphorylation of PERK and IRE1 for endoplasmic reticulum stress (ER) and phosphorylation of IRS-1 for insulin sensitivity in the liver of ob/ob mice were relieved by SalB. Further, SalB decreased phosphorylation of PERK, IRE1 and IRS1 and transcription of Bip and CHOP stimulated by palmitate of hepatic cells HL7702, but did not reversed phosphorylation of JNK and IRS1 and transcription of Bip and CHOP when ER stress was stimulated by tunicamycin. These data shows that SalB improved insulin resistance of ob/ob mice through suppression of hepatic ER stress. (C) 2020 Elsevier Inc. All rights reserved.