Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen that caused the global COVID-19 outbreak. The 3C-like protease (3CL^pro) of SARS-CoV-2 plays a key role in virus replication and has become an ideal target for antiviral drug design. In this paper, we report the validation and use of bioluminescence resonance energy transfer (BRET) technology to establish a cell-based assay for screening for SARS-CoV-2 virus 3CL protease inhibitors. The results show that the method is able to monitor the cleavage efficiency of 3CL protease with good reproducibility (Z' factor is 0.59), and is consistent with antiviral activity analysis in cell culture. This work demonstrates that this method can be applied to the screening and evaluation of 3CL protease inhibitors, providing a powerful tool for the development of new drugs.