Medicinal plants, mushrooms, and endophytes offer a rich source of secondary metabolites (SMs), including flavonoids, alkaloids, tannins, and terpenoids, with proven antiviral properties against SARS-CoV-2. Plant-associated microorganisms that colonize in living tissues of different parts of a plant possess the ability to produce SMs of immense therapeutic value and this biological interaction between plants and microbes can be exploited to develop antiviral drugs against SARS-CoV-2. The unprecedented lethality of the SARS-CoV-2 virus during the recent global pandemic has prompted extensive research into new treatment options and preventive strategies for COVID-19. Phytochemicals, particularly those derived from medicinal plants, microbes, and mushrooms, show promising results in combating the virus when combined with synthetic components. These natural compounds include terpenes, phenolics, flavonoids, and alkaloids that possess antiviral properties. Medicinal plants and their endophytic microbes, and mushrooms, offer a rich source of secondary metabolites (SMs) with potential antiviral effects against SARS-CoV-2. Given the urgency of addressing the swift spread of the new coronavirus strain, exploring and understanding these SMs could lead to the development of innovative and potent antiviral drugs. This review provides a comprehensive overview of plant-, microbial- and mushroom-derived SMs, their classification, and their applications in treating diseases caused by the coronavirus family, offering insights into the potential future production of natural medicines.