Background Coronavirus disease 2019 (COVID-19) has created the need to evaluate drugs such as favipiravir (FPV), an antiviral inhibitor of RNA-dependent RNA-polymerase (RdRp), and Maraviroc (MVC), an antiretroviral that antagonizes the chemokine receptor CCR5, which could affect the modulation of inflammation and viral replication in the treatment of COVID-19. We sought to evaluate the effect of MVC and/or FPV plus systemic steroid (SS) vs. SS alone on the viral load and progression to critical disease. Methods Sixteen patients with severe COVID-19 were evaluated in three treatment arms: 1) SS only (n=6), 2) SS plus one test drug MVC or FPV (n=5), and 3) SS plus both test drugs (MVC and FPV, n=5). The viral load was determined for N, E, and RdRp viral genes. Results A significant decrease in viral load was observed in the three treatment groups, with a larger effect size in the group that combined SS with both test drugs. The E, N, and RdRp genes with Cohen’s d were 120%, 123%, and 50%, respectively. Conclusions The largest effect on viral load reduction, as measured by effect size, was observed in the combination treatment group; however, no statistical significance was found, and it did not prevent progression to critical illness.