This study evaluated the inhibitory effects of calceolarioside B, extracted from the traditional Chinese herb Mutong (Akebia quinata Thumb), on the SARS-CoV-2 Omicron BA.2 variant. Molecular docking and molecular dynamics simulations predicted the binding sites and interactions between calceolarioside B and the Omicron BA.2 spike (S) protein. Biolayer interferometry (BLI) and immunofluorescence assays validated its high-affinity binding. Pseudovirus entry assays assessed the inhibitory effects of calceolarioside B on viral entry into host cells, while enzyme-linked immunosorbent assay (ELISA) measured inflammatory cytokine levels. Flow cytometry was used to analyze its effects on macrophage phenotype switching. Results demonstrated that calceolarioside B could bind to the Omicron BA.2 S protein with high affinity, and significantly inhibited viral entry into host cells by interfering with the binding of angiotensin-converting enzyme 2 (ACE2) receptor and S protein. Additionally, calceolarioside B reduced IL(interleukin)-6 expression levels and promoted the switch of macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. These findings suggest that calceolarioside B possesses antiviral and immunomodulatory effects, making it a potential dual-function inhibitor for the treatment of COVID-19.