To address the coronavirus disease 2019 (COVID-19) pandemic, several antiviral agents targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed for clinical use. However, antivirals that can be administered irrespective of risk factors were lacking until the approval of ensitrelvir fumaric acid (hereafter, ensitrelvir) in Japan, which took effect in November 2022. Ensitrelvir is an oral SARS-CoV-2 3C-like protease inhibitor currently approved in Japan and Singapore. This narrative review summarizes preclinical, clinical trial, and real-world data on ensitrelvir. The efficacy and safety of ensitrelvir were assessed in a seamless, randomized, double-blind, placebo-controlled, phase II/III study conducted in Japan, South Korea, and Vietnam (Japan Registry of Clinical Trials identifier, jRCT2031210350). This study enrolled patients with mild-to-moderate COVID-19 symptoms or asymptomatic individuals irrespective of the presence of risk factors for severe illness. Overall, ensitrelvir demonstrated favorable antiviral efficacy and symptom improvement, with an acceptable safety profile. In the phase III part, the time to resolution of the composite of five typical COVID-19 symptoms showed a difference between the ensitrelvir 125 mg and placebo groups, and the difference in median was approximately 1 day when the patients were randomized in less than 72 h of disease onset. This study is one of the clinical trials that used patient symptoms as a clinical efficacy endpoint. Additional clinical trials are currently underway to investigate the efficacy and safety of ensitrelvir in various patient populations. Moreover, published evidence generally supports the effectiveness of ensitrelvir in routine clinical practice and its antiviral activity against various SARS-CoV-2 variants of concern. Further research is granted to establish ensitrelvir as a novel antiviral treatment. Royalty-free licensing agreements concluded between drug manufacturers and the Medicines Patent Pool will facilitate access to COVID-19 therapeutics, including ensitrelvir, in low- and middle-income countries.