Background: Recent trials have highlighted the potential of oral antiviral VV116 in the treatment of patients with mild COVID-19. However, no comprehensive studies have assessed the safety and efficacy of VV116. Therefore, we conducted a systematic review to assess the safety and efficacy of VV116. Methods: A comprehensive search was conducted on PubMed, Scopus, and Google Scholar websites, with a cutoff date of March 23, to identify pertinent studies. Results: The results from the 3 included studies indicated that no serious adverse events were reported in the VV116 experimental groups, which exhibited a 2.57-day faster time to viral shedding than the control group and demonstrated non-inferiority to the nirmatrelvir-ritonavir control group in alleviating major symptoms. Discussion: Collectively, available studies suggest a reliable safety and efficacy profile for VV116. However, the limited number of trials was insufficient for meta-analysis, and the included population consisted of younger individuals with mild and moderate symptoms, not encompassing the elderly who are severely affected by COVID-19. We hope that more studies will be conducted in the future to ensure that VV116 has a more reliable safety and efficacy profile in the clinical setting, especially in severe or critical patients. © 2023 Lippincott Williams and Wilkins. All rights reserved.