β-Glucans, naturally occurring β-D-glucose polysaccharides from fungi, yeast, bacteria, algae, and cereals, have emerged as promising immunomodulatory agents in antiviral defense. Their structural diversity—encompassing β-1,3, β-1,6, and β-1,4 linkages—underpins varied solubility, bioavailability, and biological activity, driving their therapeutic potential. Unlike conventional antivirals that target viral replication, β-glucans enhance host immunity by activating innate and adaptive responses through receptors such as dectin-1, toll-like receptors, and complement receptor 3, thereby stimulating macrophages, neutrophils, and natural killer cells to produce antiviral cytokines (e.g., interferons, interleukins) and induce trained immunity for long-term protection. This review explores β-glucans’s mechanisms in combating viral infections, including SARS-CoV-2, HPV, HBV, influenza, and HIV, highlighting direct antiviral effects (e.g., inhibiting viral entry via sulfated derivatives), immune modulation (e.g., enhancing T-cell responses and antibody production), and inflammation control (e.g., mitigating cytokine storms). Preclinical and clinical evidence underscores their ability to reduce viral load, enhance vaccine efficacy, and support tissue repair, as seen in HPV-related lesions. β-Glucans also modulate the gut microbiota, bolstering mucosal immunity. Despite promising outcomes, challenges like structural heterogeneity and limited large-scale trials persist. This article outlines the therapeutic prospects of β-glucans, emphasizing their potential as safe and versatile adjuncts to address emerging viral threats and enhance global health resilience.