Background: Posttraumatic stress disorder (PTSD), a mental disorder induced by traumatic stress andoften accompanied by depression and/or anxiety, may involve an imbalance in the neurotransmittersassociated with the fear response. Korean Red Ginseng (KRG) has long been used as a traditionalmedicine and is known to be involved in a variety of pharmacological activities. We used the open fieldtest and forced swimming test to examine the effects of KRG on the depression-like response of rats afterexposure to single prolonged stress (SPS), leading to activation of the serotonergic system. Methods: Male rats received KRG (30, 50, and 100 mg/kg, intraperitoneal injection) once daily for 14 daysafter exposure to SPS. Results: Daily KRG administration significantly improved depression-like behaviors in the forcedswimming test, increased the number of lines crossed and time spent in the central zone in the openfield test, and decreased freezing behavior in contextual and cued fear conditioning. KRG treatmentattenuated SPS-induced decreases in serotonin (5-HT) tissue concentrations in the hippocampus andmedial prefrontal cortex. The increased 5-HT concentration during KRG treatment may be partiallyattributable to the 5-hydroxyindoleacetic acid/5-HT ratio in the hippocampus of rats with PTSD. Theseeffects may be caused by the activation of hippocampal genes encoding tryptophan hydroxylase-1 and 2mRNA levels.