It has been recognized that ginseng has anti-diabetic effects in skeletal muscle, but the mechanism has not been intensively investigated. The aim of this study was to investigate the effects of Korean red ginseng (Panax ginseng) supplementation on muscle glucose uptake in high-fat fed rats. Sixteen rats were randomly divided into two groups: a control group (CON, n = 8) and a Korean red ginseng group (KRG, n = 8). The KRG group ingested RG extract (1 g·kg(-1), 6 days/week) mixed in water for two weeks. After the two-week treatment, plasma lipid profiles, and glucose and insulin concentrations were measured. The triglyceride (TG) and glucose transporter 4 (GLUT-4) contents were measured in the skeletal muscle and liver. The rate of glucose transport was determined under a submaximal insulin concentration during muscle incubation. Plasma FFA concentrations were significantly decreased in KRG (P < 0.05). Liver and muscle triglyceride concentrations were also decreased in the KRG treatment group (P < 0.05) compared to the CON group. In addition, resting plasma insulin and glucose levels were significantly lower after Korean red ginseng treatment (P < 0.05). However, muscle glucose uptake was not affected by Korean red ginseng treatment, as evidenced by the rate of glucose transport in the epitorchealis muscle under submaximal insulin concentrations. These results suggest that while KRG supplementation could improve whole body insulin resistance and plasma lipid profiles, it is unlikely to have an effect on the insulin resistance of skeletal muscle, which is the major tissue responsible for plasma glucose handling.