Significance Drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. It has been demonstrated that a new virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions can reach an unprecedentedly high hit rate, leading to successful identification of 15 potent inhibitors of SARS-CoV-2 main protease (M ^pro ) from 25 computationally selected drugs under a threshold of K _i = 4 μM. The outcomes of this study are valuable for not only drug repurposing to treat COVID-19 but also demonstrating the promising potential of the FEP-ABFE prediction-based virtual screening approach.