The renin-angiotensin system (RAS) has an important role in the endocrine pancreas. Multiple researches have shown that even in the insulin resistance phase, there are many abnormalities in islets morphology and function. This study aimed at investigating the effects of RAS blockade on the islets function in rats with long-term high-fat diet and its mechanisms. Wistar rats with 16-week high-fat diet were randomly divided into perindopril intervention group (FP, n = 15) and telmisartan intervention group (FT, n = 15). After 8-week intervention, insulin sensitivity and islets function were detected by hyperinsulinemic euglycemic clamp and intravenous glucose tolerance test (IVGTT), respectively. The pancreases were stained by immunohistochemistry technique to qualitatively and/or quantitatively analyze the relative content of insulin (IRC), NF-KB, uncoupling protein 2 (UCP2) and caspase-3 in islets. The apoptosis of islet cells was detected by TUNEL. The expression of angiotensin II receptor 1 (AT1R), interleukin-1β (IL-1β), hypoxia-inducing factor (HIF)-1α and CHOP mRNA in the islets was detected by reverse transcription polymerase chain reaction (RT-PCR). Compared with normal control group (NC, n = 15), the glucose infusion rate (GIR), area under the insulin curve (AUCI) of 0-10 min and IRC were decreased in high-fat control group (FC, n = 15). The relative content of NF-KB, UCP-2 and caspase-3 was increased significantly with the increased number of apoptotic cells in unit islets area. The relative expression of AT1R, IL-1β, HIF-1α and CHOP was also increased evidently (all P < 0.01). After intervention, the GIR, AUCI of 0-10 min and IRC were all increased obviously with the decreased relative concentration of NF-KB, UCP-2, caspase-3 and the number of apoptotic cell in unit islets area. The relative expression of AT1R, IL-1β, HIF-1α and CHOP mRNA was reduced significantly (all P < 0.01 or P < 0.05). There were no significant differences between groups FP and FT. So we concluded that blockade of RAS may protect islet function of rats with long-term high-fat diet via downregulation of islets inflammation, oxidative stress, endoplasmic reticulum stress and apoptosis, which have tight relationship with each other.