There is a major need for antiviral drugs that are efficacious and usable for treatment of SARS-CoV-2, SARS-CoV-1, and MERS-CoV infections. One drug with strong potential to join this limited subset of efficacious in vivo oral antivirals, is Pyronaridine tetraphosphate. It has now been shown to have both in vitro and in vivo efficacy in A549 cells and K18 mice respectively by functioning as a protease inhibitor of PLpro. In our studies, Pyronaridine treatment showed significant reductions in lung inflammatory pathology, pro inflammatory cytokine and chemokine levels, and weight loss seen in the mouse model associated with severity of disease in three highly pathogenic coronavirus models. Additionally, we found that when Pyronaridine treatment was combined with Molvupiravir and Nirmatrelvir in a SARS-CoV-2 in vivo model there was evidence of a synergistic effect that further dropped viral titers, inflammatory lung pathology, and inflammatory cytokine and chemokine levels. These results indicate that Pyronaridine represents a strong potential therapeutic candidate for COVID-19 treatment individually, or in combination with other approved antivirals as well as a potential therapeutic option for treatment of other pathogenic coronaviruses such as SARS1 and MERS.