Interleucin-1β (IL-1β) is a pivotal cytokine in pro-inflammatory response induction, and it is regarded as protective in various diseases. IL-1β secretion is mainly associated with activation of the inflammasome complex, which normally is tightly regulated, depending on two signals for significant activity. The water insoluble fraction of the mushroom Ganoderma lucidum was extracted and co-cultivated with murine bone-marrow macrophages. We demonstrated that G. lucidum exopolysaccharides (EPS) were able to induce IL-1β production and release in murine macrophages. The mechanisms underlying EPS-induced priming encompass recognition through dectin-1 and activation of the spleen tyrosine kinase (Syk)/nuclear factor kappa-light-chain-enhancer of the activated B (NF-kB) axis. In addition, EPS stimulates IL-1β secretion in a phagocytosis-dependent manner via the NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in response to reactive oxygen species production, potassium efflux, phagolysosomal acidification, and cathepsin B release. Both caspase-1 and, to a lesser extent, caspase-8 were activated upon EPS stimulus and required for IL-1β cleavage and release. Lastly, EPS stimulated phagocytes' anticryptococcal activity in vitro, reducing intracellular fungal burden in dendritic cells. Moreover, oral treatment with EPS improved mice's survival in a cryptococcosis model. Our study highlighted significant stimulation by G. lucidum EPS to innate immune cells and improved its fungicidal activity, protecting the host in a murine model of infection, suggesting a potential adjuvant in antimicrobial treatment schemes.