Probiotics and their metabolites play a critical role in immunotherapy for colorectal cancer (CRC) and intestinal damage. Identifying specific probiotics from natural products and elucidating the underlying mechanisms represent promising strategies for CRC research. This study investigated the structural characterization and therapeutic potential of ginseng polysaccharides (GPS) in inhibiting tumor growth. The results showed that the molecular weight of GPS was 2425.512 kDa, which was mainly composed of Man, GluA, Gal, Glc, Xyl, and Ara contained in its structure. GPS (100, 200, and 400 mg/kg) significantly ameliorates colorectal tumorigenesis in AOM/DSS-induced and MC38-induced CRC models. 16S rRNA shows that GPS supplementation significantly increased the abundance of Lachnospiraceae compared to the model group. Mechanistically, GPS supplementation promoted the proliferation of beneficial Lachnospiraceae bacterium (L.B.), leading to increased short-chain fatty acids (SCFAs) production. The effective anti-CRC effects of key probiotics were further substantiated by their ability to inhibit myeloid-derived suppressor cells (MDSCs) and enhance the infiltration and activation of CD8