Fungi are ubiquitous organisms that are capable of transient or persistent colonization in humans. Their polymorphic nature and complex host–mycobiome interactions remain incompletely understood. Emerging evidence highlights the role of resident fungi in modulating immune responses and adapting to host changes, which can trigger a shift from commensalism to parasitism, particularly in immunocompromised individuals. This study evaluated the effects of two major β-glucans—zymosan and curdlan—on the expression of pattern recognition receptors (Dectin1, Dectin2, TLR2, TLR4) in human peripheral blood mononuclear cells (PBMCs). It also examined their impact on reactive oxygen species (ROS) production, cytokine/chemokine gene expression, and antioxidant enzyme expression. Both β-glucans significantly increased the mRNA levels of all tested receptors and enhanced ROS generation. Curdlan downregulated key antioxidant enzymes (SOD1, CAT, GPX1), while zymosan markedly upregulated SOD1. These findings demonstrate that the β-glucans zymosan and curdlan have a substantial influence on PBMC reactivity and oxidative stress responses. Further studies are needed to deepen our understanding of host–fungal interactions and their implications in health and disease.