Despite the development of Coronavirus Disease 2019 (COVID-19) vaccines, the search for a definitive cure continues. 6'-Hydroxy justicidin B (6'-HJB), found in Justicia procumbens and used in Chinese medicine for its antiviral properties, shows promise as a therapeutic candidate against COVID-19. Nevertheless, it is crucial to establish its safety profile before clinical trials. This study evaluated its safety through non-clinical Good Laboratory Practice genotoxicity and rodent toxicity studies. The results indicated that 6'-HJB is not genotoxic, supporting its safety for future clinical use. The compound exhibited a low risk of DNA damage, a critical concern in drug development. Extensive toxicity studies, including single and repeated oral doses in Sprague Dawley rats, showed that the lethal dose of 6'-HJB exceeded 2000 mg/kg, with no observed adverse effects at this level. Safety data from genotoxicity and rodent toxicity studies strongly support further investigation of 6'-HJB as a novel treatment for COVID-19. 6'-HJB is expected to serve as a promising therapeutic option for overcoming future emerging viral infectious diseases.