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Introduction: Artemisia annua L. is an antidiabetic plant that was reported to exhibit an improving effect on insulin resistance in type 2 diabetes conditions but its cellular mechanisms was unclear. So, this study aims to explore the role of Artemisia annua extract in PI3K (phosphatidylinositol 3-kinase)/ AKt (serine/threonine kinase protein B) signaling pathway in liver of high-fat diet (HFD)/Streptozotocin (STZ)-induced type 2 diabetic mice. Methods and Materials: Mice were randomly divided into groups: control, untreated diabetic mice, diabetic mice treated with various doses (100, 200, 400 mg/kg) of alcoholic extract of Artemisia annua and metformin for 4 weeks. Type 2 diabetes was induced by feeding high-fat diet and low dose of STZ injection. After experiment duration, all mice were sacrificed following a deep anesthesia to measure the level of blood glucose, insulin, homeostasis model assessment of insulin resistance index (HOMA-IR), and liver tissues were isolated for to detect m-RNA expression of PI3K and Akt in insulin signaling pathway. Results: Metformin significantly reduced the blood level of glucose, insulin and HOMA-IR in treated diabetic mice compared to untreated diabetic mic. Alcoholic extracts of this plant markedly reduced hyperglycemia, hyperinsulinemia, HOMA-IR in treated diabetic mice compared to untreated diabetic mice. In addition, they could up-regulate the expression of PI3K and AKt m-RNA in liver tissues in diabetic mice. Doses of 200 and 400 of extract were similar to metformin effect on AKt and PI3K m-RNA expression. Conclusion: The alcoholic extract of Artemisia annua ameliorated insulin resistance and increased insulin sensitivity via activation of PI3K/AKt signaling pathway in diabetic liver. So, it can be a suitable alternative treatment with fewer complications to synthetic antidiabetic drugs to improve insulin resistance in type 2 diabetes condition. [ABSTRACT FROM AUTHOR]