<i>Tricholoma mongolicum</i> is a well-known edible and medicinal mushroom that is rich in protein, polysaccharides, and other nutrients and is found in China's Inner Mongolia region, which has a variety of pharmacological activities. In this study, the water-soluble protein extract of <i>T. mongolicum</i> (WPTM) were assessed. Further, the anti-tumor activity of the water-soluble protein extract of <i>T. mongolicum</i> (WPTM) in H22 tumor-bearing mice was investigated in this study. The H22 anti-tumor activity of<i> T. mongolicum</i> protein was studied. WPTM significantly improved interferon-γ, interleukin-2, interleukin-6, and tumor necrosis factor-α levels in serum cytokine, but decreased vascular endothelial growth factor (VEGF) levels. And WPTM treatment of H22 tumor tissues significantly increased the expression levels of BAX and caspase-3 but decreased those of Bcl-2 and VEGF in a dose-dependent manner. In summary, the findings indicate that<i> T. mongolicum</i> is a protein-rich edible and medicinal fungus that is a potential functional food for the prevention and treatment of liver cancer.<i> T. mongolicum</i> has a high protein content and nutritional value, as well as anti-tumor properties, and is expected to be widely developed.