Introduction: Hypericum perforatum L. (St. John\\\\\\\\\\\\\\\'s wort) is a member of Hypericaceae family and an herbaceous perennial plant native to North Africa, Western Europe, Asia, and North America. This pharmaceutical plant has many features such as antidepressant, antitumor, antiviral and anti-inflammation. The antiviral and anti-inflammatory effects of this plant depend on the presence of two active ingredients; hypericin and hyperforin. In this review, we provide a broad overview of recent advances in the extraordinary effects of the Hypericum perforatum extract (consist of hypericin and hyperforin) on HIV, IAV, and SARS-CoV-2. Methods: For this review article, all information was obtained in the English, German, Persian, French languages from search engines including Google Scholar, PubMed, Science Direct, Research Gate, and Embase. We used published articles until December 2020. Results: Based on research, the antiviral effects of this plant are related to hypericin. Nonetheless, hypericin can only inactivate the viruses endowed with coats. A certain concentration of hypericin could inactivate HIV-1 in vitro and in vivo. hypericin interferes with the processing of the HIV Gag polyprotein (p55) and HIV p24 (main capsid protein). This function causes the production of immature or abnormally assembled cores, therefore; the virus is not able to encode viral antigens in infected cells and lost its infectivity. Some studies reported that hypericin by binding to main regions of SARS-CoV-2 can prevent virus assembly and infection. In IAV-infected mice, Hypericum perforatum extract can decrease the lung index and the secretions of TNF-α and IL-6 in serum and lung tissue. According to the new research, hyperforin is the main component that has anti-inflammatory effects and regulates immune system function. hyperforin prevent further cytokine production such as IL-1β, TNF-α, IL-6 and chemokines through the simultaneous inhibition of JAK/STAT (the Janus kinase/signal transducer and activator of transcription), MAPK (mitogen-activated protein kinases), NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathways. Therefore, these mechanisms can limit the effects of the cytokine storm and prohibit severe local and systemic inflammation. Conclusion: In some virus diseases, excess release of pro-inflammatory cytokines, imbalance in the regulatory mechanisms of the immune system, and spreading of viral infection cause exacerbation of the disease and even death. For instance, in COVID-19 patients, cytokine storm plays a major role in the death. We believe hyperforin through the inhibition of three main signaling pathways (JAK/STAT, MAPK, NF-κB) and hypericin due to its antiviral effects against coated viruses may be able to inhibit this kind of disease. In our opinion, Hypericum perforatum extract (consist of hypericin and hyperforin) can be used as a suggested option for the treatment. Although; this suggestion requires further research and clinical trials

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