Ginseng root residue, a by-product obtained during ginseng beverage processing, was shown to contain a high amount of ginsenosides. This study aims to prepare nanoemulsion and liposome from American ginseng root residue extract (AGRE-NE and AGRE-LP) for evaluation of anti-fatigue effects in rats. The AGRE-NE was prepared by mixing an appropriate ratio of ginseng root residue extract, soybean oil, lecithin, Tween 80 and deionized water, while the AGRE-LP prepared by a suitable ratio of ginseng root residue, extract, Tween 80, phosphatidylcholine, cholesterol, PEG400 and deionized water. Based on dynamic light scattering and transmission electron microscopic methods, the mean particle size was 10.4 and 12.3 nm for AGRE-NE respectively, while 53.5 and 61.2 nm for AGRE-LP. Also, both AGRE-NE and AGRE-LP showed a high stability over a 90-day storage period at 4 and 25°C, but the former possessed a lower stability at 80 and 100°C. The anti-fatigue experiment using a swimming rat model with caffeine as positive control demonstrated an extension of exhaustive swimming time and elevation of hepatic glycogen as well as a decline in both blood urea nitrogen and lactic acid levels, following administration with high and low doses of ginseng root residue extract, AGRE-NE and AGRE-LP. By comparison, both AGRE-NE and AGRE-LP showed a pronounced anti-fatigue effect in rats, with a great potential to be developed into a functional food or even a botanic drug.