As the COVID-19 pandemic continues to pose a health risk concern to humans, despite a significant increase in vaccination rates, an effective prevention and treatment of SARS-CoV-2 infection is being sought worldwide. Herbal medicines have been used for years and played a tremendous role in several epidemics of respiratory viral infections. Thus, they are considered as a promising platform to combat SARS-CoV-2. Previously, we reported that common dandelion (Taraxacum officinale) leaf extract and its high molecular weight compounds strongly suppressed in vitro lung cell infection by SARS-CoV-2 Spike D614 and Delta variant pseudotyped lentivirus. We now here demonstrate that T. officinale extract protects against the most prominent Omicron variant using hACE2-TMPRSS2 overexpressing A549 cells as in vitro model system. Notably, compared to the original D614, and the Delta variant, we could confirm a higher efficacy. Short-term interval treatment of only 30 min was then sufficient to block the infection by 80% at 10 mg/mL extract. Further subfractionation of the extract identified compounds larger than 50 kDa as effective ACE2-Spike binding inhibitors. In summary, the evolution of SARS-CoV-2 virus to the highly transmissible Omicron variant did not lead to resistance, but rather increased sensitivity to the preventive effect of the extract.