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Despite the great success of vaccines that protect against RNA virus infections, and the development and clinical use of a limited number of RNA virus-specific drugs, there is still an urgent need for new classes of antiviral drugs against circulating or emerging RNA viruses. To date, it has proved difficult to efficiently suppress RNA virus replication by targeting host cell functions, and there are no approved drugs of this type. This opinion article discusses the recent discovery of a pronounced and sustained antiviral activity of the plant-derived natural compound thapsigargin against enveloped RNA viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), and influenza A virus. Based on its mechanisms of action, thapsigargin represents a new prototype of compounds with multimodal host-directed antiviral activity. The hexa-oxygenated guaianolide thapsigargin profoundly suppresses the replication of various human coronaviruses (CoVs), respiratory syncytial virus (RSV), and influenza A virus (IAV) at low concentrations. In virus-infected cells, thapsigargin activates endoplasmic reticulum (ER) stress, improves the biosynthetic metabolic state, and inhibits autophagy pathways. During viral infection, thapsigargin upregulates proteins involved in ER-associated protein degradation (ERAD), ER quality control (ERQC), intracellular membrane fusions, and membrane rearrangements. Thapsigargin has antiviral activity in animal models of IAV infection. The multimodal antiviral actions of thapsigargin define a new prototype of host-directed broad-spectrum antiviral drugs that efficiently suppress the replication of enveloped RNA viruses. [ABSTRACT FROM AUTHOR]