Viral outbreaks and pandemics have created an increasing interest in finding new antiviral compounds from natural sources that offer a broad spectrum of pharmacological properties. Fungal secondary metabolites play an extensive role in human health and disease. The efficiency of fungi to adjust to various fermentation conditions makes them potent novel drug candidates. Only 3–8% of fungal species have been explored for their pharmacological activities, representing a significant gap in our understanding of their full potential. Ascomycota and Basidiomycota are the primary reservoirs of diverse fungal secondary metabolites (FSMs) with immunomodulatory and antiviral activities. These effects are largely mediated by modulating the cytokine production in the immune system. Fungal metabolites such as indole alkaloids (IA), non-ribosomal peptides (NRPS), polyketides (PKS), and terpenoids have been widely discussed for their antiviral activities against a wide variety of viruses, including Herpes simplex virus (HSV), Influenza A Virus (IAV), and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The chapter discusses recent advancements in the area of immunomodulatory and antiviral activities of fungal secondary metabolites. It further emphasizes their mechanisms of action, synergistic effects in combination therapies, and the associated challenges.