In this study, biological active compounds (ginsenoside Re and Rc) found in Panax ginseng were investigated in the evaluating for glucose uptake abilities using C2C12 myotubes. Both ginsenoside Re and Rc significantly increased glucose uptake in the cells. To identify the specific target of ginsenoside Re and Rc, we next examined the possibility of involvement of AMP‐activated protein kinase (AMPK) signaling in the glucose uptake ability of ginsenoside Re and Rc. In our experiments, ginsenoside Re and Rc increased glucose uptake was accompanied by AMPK activation in the C2C12 skeletal muscle cells. AMPK plays a beneficial role in the prevention of metabolic disorder as diabetes. Moreover, the inhibition of AMPK signaling pathway significantly abrogated both ginsenoside Re and Rc stimulated glucose uptake. These results indicated that AMPK activation was critical for the glucose uptake stimulated by ginsenosides. Collectively, our results suggest that both ginsenoside Re and Rc may exert anti‐diabetic effects in skeletal muscle cells through the AMPK signaling pathway. Thus, the AMPK might be useful in the treatment of diabetes mellitus by using active components derived from natural compounds.