Coronavirus disease 2019 (COVID-19) represents an unmet clinical need, due to a high mortality rate, rapid mutation rate in the virus, increased chances of reinfection, lack of effectiveness of repurposed drugs and economic damage. COVID-19 pandemic has created an urgent need for effective molecules. Clinically proven efficacy and safety profiles have made favipiravir (FVP) and remdesivir (RDV) promising therapeutic options for use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Even though both are prodrug molecules with an antiviral role based on a similar mechanism of action, differences in pharmacological, pharmacokinetic and pharmacotoxicological mechanisms have been identified. The present study aims to provide a comprehensive comparative assessment of FVP and RDV against SARS-CoV-2 infections, by centralizing medical data provided by significant literature and authorized clinical trials, focusing on the importance of a better understanding of the interactions between drug molecules and infectious agents in order to improve the global management of COVID-19 patients and to reduce the risk of antiviral resistance.