Polysaccharides isolated from mushrooms have been identified as potential prebiotics that could impact gut microbiota. In this study, a water-soluble polysaccharide (MP) extracted from wild morels was evaluated for its effects on the gut microbiota of non-treated and cyclophosphamide (CP)-treated mice. The results showed that MP restored the spleen weight and increased the counts of white blood cells and lymphocytes in the peripheral blood and spleen of the CP-treated mice. Mice treated with MP exhibited increased levels of short-chain fatty acid (SCFA)-producing bacteria, especially Lachnospiraceae, compared to normal mice, and increased levels of Bacteroidetes and SCFA-producing bacteria, especially Ruminococcaceae, compared to the CP-treated mice. Moreover, MP treatment increased the production of valeric acid and decreased the production of acetic acid in the non-treated mice and increased the production of acetic acid, propionic acid, butyric acid, and valeric acid in the CP-treated mice. These results show that MP is potentially good for health.