The immunostimulatory role of the polysaccharide fraction (KRG-P) of Korea red ginseng (KRG) was studied in cells. However, its immunomodulatory activity is unknown. Therefore, we investigated the chemical properties of KRG-P and its intestinal immune responses in vitro and in vivo. (2) Methods: KRG-P monosaccharide composition and molecular weight were determined using high-performance liquid and size-exclusion chromatography systems. Immunoglobulin A (IgA) and α-defensin-1 transcript levels were measured using a SYBR Green qRT-PCR; defensin-1, Granulocyte-macrophage colony-stimulating factor (GM-CSF), and IgA protein levels were determined using Western blotting and ELISA kits. (3) Results: The molecular weight of KRG-P was estimated to be 106 kDa, and it contained neutral sugar (74.3%), uronic acid (24.6%), and proteins (1%). In vitro studies of intestinal immunomodulatory activity of KRG-P indicated that GM-CSF and IgA levels increased in Peyer’s patch cells to higher levels than those obtained with KRG and induced bone marrow cell proliferation. In in vivo study, oral KRG-P administration to mice upregulated the expression of α-defensin-1 and IgA in the small intestinal tissue and that of secreted IgA in the feces. (4) Conclusions: KRG-P contributed to the modulation of intestinal immunity and maintenance of intestinal homeostasis against intestinal infection.