Many dietary flavonoids exist as glycosides in fruits and vegetables, and they are considered as bioactive food components potentially responsible for various health benefits. Type 2 diabetes mellitus is a complex and polygenic disease with increasing global prevalence. In this study, the inhibitory effects of avicularin (quercetin‐3‐O‐α‐arabinofuranoside), a flavonoid glycoside commonly found in apple and mango, were determined in the mice with high fat diet/streptozotocin induced type 2 diabetes. Our results demonstrated that dietary avicularin treatment (100 mg/kg/d) reduced levels of fasting blood glucose, TG and LDL‐C, improved β‐cell function, and suppressed hepatic steatosis in diabetic mice. Gene expression analysis by RNA‐Seq revealed that arachidonic acid metabolism, drug metabolism‐cytochrome P450, drug metabolism‐other enzymes, MAPK signaling pathway, metabolic pathways, metabolism of xenobiotics by cytochrome P450, p53 signaling pathway and retinol metabolism were the major pathways altered in the liver of the diabetic mice in comparison with that of the negative control mice (healthy mice). Within the type 2 diabetes mellitus related pathways, ADIPO, P13K, SOCS, VDCC, SUR1, GK, PYK genes were upregulated in diabetic mice compared to the healthy mice, and avicularin treatment significantly downregulated these genes in the diabetic mice. Within the PPAR pathways, the mRNA levels of FABP1, SCD‐1, SCP‐X, ADIPO, PEPCK were increased in the diabetic mice, and avicularin treatment effectively decreased the levels of these gens in the diabetic mice. Avicularin treatment also upregulated the genes such as CYP7A1, CYP8B1, and CYP4A1 that was downregulated in the diabetic mice in comparison with the healthy mice. Taken together, our results demonstrated the protective effects of avicularin against diabetes and provided a global view of the effects of avicularin on the complexity transcriptome in diabetic mice. Support or Funding Information This study was supported by the University of International Cooperation in Science and Technology Innovation Platform Project of Guangdong (2013gjhz0003), the Education Department of Guang zhou Province (Grant No. 2013J4100075), the National Natural Science Foundation of China (Grant No. 31201321).