There is currently no standardized treatment of COVID-19. Despite several vaccines being deployed, the need for an effective treatment in hospitalized patients is heavily sought after. In this systematic review, six clinical trials were analyzed for their findings on the effect of commercially available anti-viral protease inhibitors in treatment of COVID-19. The aim of the study was to evaluate the effect on the hospitalization period and mortality of patients suffering from COVID-19 and if HIVprotease inhibitors could be repositioned to treat COVID-19 in combinational therapy. The findings suggest that protease inhibitors targeting the hepatitis C virus (HCV) proteases could potentially beeffective at reducing the hospitalization period and that the effect can be further enhanced by using them in combination with drugs targeting the RNA polymerases. Further studies are needed confirm these findings. Lopinavir/ritonavir which was the most common protease inhibitor included in the study did not reduce the hospitalization period or the mortality significantly. It is unclear whether the HCV protease inhibitors could reduce mortality. Further studies regarding this outcome are warranted.