American ginseng (Panax quinquefolium L.) contains pharmacologically active secondary compounds known as ginsenosides, which have been shown to be affected by both genetic and environmental factors. In this greenhouse experiment, we tested the hypothesis that ginsenosides would behave as “stress metabolites” and be associated with osmoregulation in response to drought stress. Two year-old seedlings, grown in 5-inch pots, were well watered for 40 days prior to the initiation of treatments. Plants in the drought stress treatment were watered every 20 days while the controls were watered every 10 days, and the experiment was terminated after 4 and 8 dry down cycles (80 days), respectively. Predawn leaf water potential and relative water content (RWC) of drought-stressed plants during a typical dry down cycle were lower than control plants. The diameter and weight of primary storage roots were decreased in the stressed treatment. The length of the main storage root and the longest secondary (fibrous) root were significantly increased by the drought stress treatment. Leaf chlorophyll content of drought-stressed plants was lower than controls. The osmotic potential of the drought-stressed ginseng was not lower than the control, indicating that ginsenoside is not involved in osmoregulation in response to drought stress. Furthermore, ginsenosides Rb1 and Rd, and total ginsenosides were significantly lower in primary roots of drought-stressed plants compared to control plants.