Since the high mobility group box-1 (HMGB1) molecule had been recognized as a proinflammatory cytokine, which mediates endotoxin lethality of mice, there have been lots of papers about targeting the HMGB1 within the contexts of infection, inflammation, and cancer. The pathogenic impact of HMGB1 to the severe acute respiratory syndrome (SARS) and disease management with herbal formulations targeting this unique protein have already been proposed. However, the failure of the numerous current anti-viral therapies on the ongoing viral infections casts reappraisal of the possible interrelationships regarding the HMGB1 and SARS-CoV-2. COVID-19 pandemic due to the SARS-CoV-2 virus is a currently ongoing challenging global health crisis. There is still not any proven exact treatment of COVID-19 with high level of evidence. In this paper, we focused on the potential usage of external and/or inhalation preparation of antiviral/antibacterial herbal products capable of targeting HMGB1 for the clinical management candidates of the ongoing COVID-19 infection.