BACKGROUND: Developing antiviral agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a global goal since the Coronavirus Disease 2019 (COVID-19) pandemic emerged in 2019. Korean Red Ginseng (KRG), recognized for its immunomodulating and antiviral properties, may be effective against SARS-CoV-2. Therefore, we aimed to investigate the efficiency of KRG in a human angiotensin-converting enzyme 2 (hACE2)-expressing mouse model infected with pseudo-typed SARS-CoV-2 (PSV). METHODS: The lung injury score was assessed using H&E staining, and the immune cell population shift in the lung and spleen was observed through flow cytometry. Serum IgM and IgG concentrations were quantified using enzyme-linked immunoassay (ELISA). Pro-inflammatory cytokine levels were measured by cytometric bead assay (CBA) and polymerase chain reaction (PCR). Additionally, the expression of NLR family pyrin domain containing 3 (NLRP3) and inflammation-related transcription factors was detected by immunoblotting. RNA-sequencing and antibody array assays reconfirmed gene expression in inflammation and oxidation. RESULTS: KRG extract was most effective in treating lung injuries and serum IgM and IgG levels. Also, immune cells, including neutrophils, were regulated in the lungs, and tumor necrosis factor-alpha (TNF-a) levels were reduced. NLRP3 and phosphorylated nuclear factor-κB (NF-kB) and activator protein 1 (AP-1) were downregulated. Heme oxygenase-1 (HO-1) expression was increased, indicating that KRG extract has antioxidant properties. RNA-sequencing and antibody array assays revealed that KRG extract regulates the expression of genes associated with inflammation and oxidative damage. CONCLUSIONS: This study demonstrates that KRG extract may suppress PSV-induced inflammation and oxidative stress, making it a viable antiviral functional food.