Pyronaridine reduces infection against multiple Omicron subvariants of SARS-CoV-2. Wild-type 8- to 10-week-old BALB/c mice were treated with molnupiravir (oral administration) or pyronaridine(oral administration) daily at the indicated concentrations starting 12 h before infection. Mice (n = 5 per group over two independent experiments) were intranasally inoculated with 1 × 105 PFU per mouse of SARS-CoV-2 Omicron (BA.1 for A–D, and BA.5 for E–H). Mice were weighed daily (A and E), and lungs were analyzed for viral titer 2 and 4 days after infection by plaque assay (B and F), or fixed in 4% paraformaldehyde for H&E staining (C and G) and quantified for lung inflammation (D and H). n = 5 mice per group. Mean ± SD is shown. *P < 0.05, **P < 0.01, and ***P < 0.001, using two-way analysis of variance with Tukey’s multiple comparison test. The red asterisks are compared to virus-only group.