Abstract: Objective: For the extraction of polysaccharides from American ginseng fruits, the extraction process was optimized in combination with response surface methodology, and to investigate whether polysaccharides from American ginseng fruits had antioxidant activity in vitro. Methods: In this study, polysaccharides were extracted from fresh American ginseng fruits by water extraction and alcohol precipitation method. The extraction process was optimized using single factor tests as well as response surface methodology. In vitro antioxidant activity studies of polysaccharides from American ginseng fruits were conducted from three aspects: DPPH radical scavenging rate, hydroxyl radical scavenging rate as well as reducing power. Results: The optimal process parameters were as follows: the extraction time was 2.5 h, the concentration of ethanol was 80%, the feed to liquid ratio of 1:16 g/mL, and the measured average value of polysaccharide yield was 29.47%±0.65%, which was comparable to the model predicted value. In vitro antioxidant activities of polysaccharides from American ginseng fruits were examined in the following three aspects. When the concentration of polysaccharides was 3.4 mg/mL, the DPPH radical scavenging rate was 75.14%±0.65%, and IC₅₀ value was 0.71 mg/mL. When the concentration of polysaccharide was 3.4 mg/mL, the scavenging rate against hydroxyl radicals could reach 71.82%±1.43%, and IC₅₀ value was 0.87 mg/mL. When the concentration of polysaccharides was 1.0 mg/mL, the total reducing power reached 0.730, and its in vitro antioxidant capacity was enhanced with increasing concentrations of polysaccharides from American ginseng fruits. Conclusion: The experimental results of antioxidant activities illustrated that polysaccharides from American ginseng fruits had better antioxidant activities. This study may provide a theoretical basis for further development and utilization of polysaccharides from American ginseng fruits, and ensure that traditional Chinese medicine resources can be fully utilized.