This study enhanced germanium (Ge) enrichment in the liquid fermentation of the edible fungus Lyophyllum decastes in order to boost its biological activity, particularly its antioxidant and immunomodulatory properties. Through the use of single-factor and Plackett–Burman designs, the experiments revealed critical parameters affecting Ge enrichment, including Ge oxide concentration, potato powder concentration, and peptone levels. The optimization of the Box–Behnken response surface methodology resulted in a Ge concentration of 3.61 mg/L, significantly enhancing the biomass, protein, polysaccharide, and flavonoid content in the mycelium. In contrast to traditional fermentation, Ge-rich fermentation enhanced the mycelial biomass by 30.97% and elevated the organic Ge content 50.19-fold. An analysis of the antioxidants revealed that the Ge-enriched mycelial water extract exhibited heightened activity, augmenting TNF-α production in RAW264.7 cells by 73.29% at a concentration of 200 μg/g. These findings indicate that the Ge-enriched fermentation of L. decastes holds promise for functional applications in health-supportive products due to its robust antioxidant and immune-enhancing capabilities.