Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel strain that causes acute respiratory illnesses known as coronavirus disease 2019 (COVID-19). Currently, there is limited information regarding the therapeutic management for this disease. Several studies have stated that antivirals drugs such as remdesivir, favipiravir, and lopinavir/ritonavir may potentially inhibit the virus from spreading to the host. Objective: The aim of this systematic review was to summarize the clinical effectiveness and safety of remdesivir, favipiravir, and lopinavir/ritonavir on COVID-19. Methods: The PubMed and Cochrane Library databases were searched up to July 2021 to identify eligible experimental randomized controlled trials on remdesivir, favipiravir, and lopinavir/ritonavir for COVID-19 patients. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Results: From 158 references, 15 studies were included in the review. The results showed that remdesivir has some potential benefits for hospitalized COVID-19 patients, as seen from clinical improvements such as faster recovery time, less duration of hospitalization, and fewer respiratory side effects among COVID-19 patients. However, the impact of remdesivir in reducing mortality remains uncertain. Treatment with favipiravir has shown promising improvement in the clinical status of COVID-19 patients, although the results suggested no significant differences in some clinical parameters such as length of hospitalizations and clinical recovery. A combination of favipiravir with other supportive therapy showed more favorable outcomes for COVID-19 patients. Furthermore, the use of lopinavir/ritonavir in COVID-19 patients reported no significant clinical improvement compared to standard care with notable adverse effect reactions. Conclusion: This study provides an overview of the evidence-based role of remdesivir, favipiravir, and lopinavir/ritonavir in the management of COVID-19. A thorough assessment of the benefit-risk profile in COVID-19 patients is urgently needed. The current review was based on very limited available data; therefore, further well-designed clinical trials are required.