Background and Purpose Codonopsis lanceolata (CL) has long been used as a medicinal herb in East Asian countries to treat inflammatory diseases of the respiratory system but its antiviral activity has not been investigated. Here, we evaluated the potential inhibitory activity of CL extracts and their active compounds on SARS-CoV-2. Experimental Approach Pseudotyped SARS-CoV-2 entry assay and dose-response curve analysis with authentic SARS-CoV-2 and recombinant SARS-CoV-2 reporter virus expressing the nanoluciferase were carried out to investigate the effects of compounds against SARS-CoV-2 entry into host cells. Filipin cholesterol staining, SARS-CoV-2 Spike (S)-ACE2 binding assay, and S-mediated cell fusion assay using time-lapse imaging, flow cytometry, and split-GFP fusion were conducted to understand the inhibitory mechanisms. Key Results Lancemaside A (LA), a triterpenoid saponin isolated from CL, impeded the endosomal entry pathway of SARS-CoV-2 and its variants including Alpha, Beta, Delta, and Omicron with similar IC50 values of 2.23 ~ 3.37 μM as well as the TMPRSS2-mediated viral entry pathway with IC50 value of 3.92 μM. LA was also able to prevent the formation of S-induced multinucleated syncytia. Mechanically, LA altered the distribution of host cell membrane cholesterol and blocked the membrane fusion between SARS-CoV-2 and host cells. Conclusion and implications LA can be a broad-spectrum antiviral drug not only against SARS-CoV-2 but also against other novel enveloped viral pathogens that might arise in the future by targeting viral envelope fusion with the host cell membrane. Keywords SARS-CoV-2, Omicron, COVID-19, Lancemaside A, triterpenoid saponin, membrane fusion