The present disclosure discloses a novel coronavirus SARS-COV-2 safe replicon system and use thereof in screening an anti-SARS-COV-2 drug. The safe replicon system specifically comprises a nucleic acid sequence encoding a novel coronavirus SARS-COV-2 non-structural protein; and nucleic acid sequences of 5′ UTR and 3′ UTR of a novel coronavirus SARS-COV-2, a transcription regulatory region on which the novel coronavirus SARS-COV-2 non-structural protein can act, and a reporter gene. With the SARS-COV-2 safe replicon system, high-throughput screening of anti-SARS-COV-2 drugs and pharmacologic verification of drugs can be carried out independent of a biosafety level 3 laboratory, and the operation is simple and convenient.