| Summary: | (1) Background: Viral respiratory infections cause life-threatening diseases in millions of people worldwide every year. Human coronavirus and several picornaviruses are responsible for worldwide epidemic outbreaks, thus representing a heavy burden to their hosts. In the absence of specific treatments for human viral infections, natural products offer an alternative in terms of innovative drug therapies. (2) Methods: We analyzed the antiviral properties of the leaves and stem bark of the mulberry tree (<i>Morus</i> spp.). We compared the antiviral activity of <i>Morus</i> spp. on enveloped and nonenveloped viral pathogens, such as human coronavirus (HCoV 229E) and different members of the <i>Picornaviridae</i> family—human poliovirus 1, human parechovirus 1 and 3, and human echovirus 11. The antiviral activity of 12 water and water–alcohol plant extracts of the leaves and stem bark of three different species of mulberry—<i>Morus alba</i> var. <i>alba</i>, <i>Morus alba</i> var. <i>rosa</i>, and <i>Morus rubra</i>—were evaluated. We also evaluated the antiviral activities of kuwanon G against HCoV-229E. (3) Results: Our results showed that several extracts reduced the viral titer and cytopathogenic effects (CPE). Leaves’ water-alcohol extracts exhibited maximum antiviral activity on human coronavirus, while stem bark and leaves’ water and water-alcohol extracts were the most effective on picornaviruses. (4) Conclusions: The analysis of the antiviral activities of <i>Morus</i> spp. offer promising applications in antiviral strategies.
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