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Ultrasonic-assisted extraction (UAE) of American ginseng polysaccharides (AGP) was investigated using response surface methodology. Three-factor-three-level Box-Behnken design was employed to optimize the ultrasonic power, extraction time and ratio of water to raw material to obtain a high AGP yield. The analysis of variance and response surface plots indicated that ultrasonic power was the most important factor affecting the extraction yield. The optimal conditions were ultrasonic power 400 W, extraction time 71 min, and ratio of water to raw material 33 mL g-1. Under these conditions, the yield of AGP was 8.09%, which was agreed closely to the predicted value. Gas chromatography (GC) analysis showed that AGP was composed of arabinose, rhamnose, galactose, glucose, and galacturonic acid. Fourier transform infrared spectra revealed the general characteristic absorption peaks of AGP. In addition, AGP exhibited good immunostimulating activities by up-regulating the production of nitric oxide and cytokines. Compared with hot water extraction, UAE required shorter extraction time and gave a higher extraction yield, without changing the structure and immunostimulating activity of AGP. The results indicated that UAE could be an effective and advisable technique for the large scale production of plant polysaccharides.