Display omitted •IHN is a plant flavonoid with anti-diabetic properties.•We assessed the insulin resistance lowering effects of IHN in T2DM rat.•IHN resulted in restoration of myofibrils and adipose tissue architecture.•IHN down regulates mTOR,IGF1-R & LncRNA-RP11-773H22.4 expression.•IHN up-regulates the expression of AKT2 mRNA, miR-1, and miR-3163. We intended to examine the molecular mechanism of action of isorhamnetin (IHN) to regulate the pathway of insulin signaling. Molecular analysis, immunofluorescence, and histopathological examination were used to assess the anti-hyperglycemic and insulin resistance lowering effects of IHN in streptozotocin /high fat diet-induced type 2 diabetes using Wistar rats. At the microscopic level, treatment with IHN resulted in the restoration of myofibrils uniform arrangement and adipose tissue normal architecture. At the molecular level, treatment with IHN at three different doses showed a significant decrease in m-TOR, IGF1-R & LncRNA-RP11-773H22.4. expression and it up-regulated the expression of AKT2 mRNA, miR-1, and miR-3163 in both skeletal muscle and adipose tissue. At the protein level, IHN treated group showed a discrete spread with a moderate faint expression of m-TOR in skeletal muscles as well as adipose tissues. We concluded that IHN could be used in the in ameliorating insulin resistance associated with type 2 diabetes mellitus.