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The escalating pandemic brought about by the novel SARS-CoV-2 virus is threatening global health, and thus, it is necessary to develop effective antiviral drugs. Usenamine A is a dibenzo-furan derivative separated from lichen Usnea diffracta showing broad-spectrum activity against different viruses. We evaluate that usenamine A has antiviral effects against novel SARS-CoV-2 Delta variant pseudotyped viruses (PVs) in A549 cells. In addition, usenamine A significantly suppresses SARS-CoV-2 PV-induced mitochondrial depolarization, elevated reactive oxygen species (ROS) levels, apoptosis, and inflammation. Usenamine A also causes the SARS-CoV-2 spike protein to become less stable. Thus, usenamine A shows potential as an antiviral drug that can provide protection against COVID-19.