Background: Overconsumption of High fructose diet (HFD) is one of the major contributors to the current epidemic of insulin resistance (IR). Autophagy is the natural, regulated, destructive mechanism of the cell that destroys unnecessary or dysfunctional components and turnover these destroyed cell organelles for new cell formation that maintains homeostasis. Caloric restriction (CR) is one of the physiological triggers of autophagy Aim: This study aimed to investigate the effect of moderate CR on IR induced by HFD in rats and to explore the role of autophagy in this process. Methods: 48 adult Wistar albino male rats divided into 2 main groups: control group, IR group. Then IR group is classified into 4 subgroups: group IIa received HFD for 10days, group IIb received moderate caloric diet 40% CR, group IIc received moderate caloric diet + spermidine "an autophagy inducer "and group IId received moderate caloric diet + chloroquine "an autophagy inhibitor". At the end of the experiment, the body mass index (BMI) was calculated; fasting glucose, insulin were measured and HOMA-IR was estimated. Then, biopsies of pancreas and liver are taken for both biochemical estimations of tissue beclin-1(BCL-1) mRNA & histopathological examination. Results: HFD caused a significant increase in BW, BMI, HOMA-IR & pancreatic BCL-1 mRNA expression, with a significant decrease in hepatic BCL-1 mRNA expression. Moderate CR revered these effects through induction of hepatic autophagy. Conclusion: CR showed a protective effect against the HFD induced IR that can be explained by induction of autophagy in hepatic tissue.