The emergence of SARS-CoV-2 variants necessitates innovative antiviral strategies. This study demonstrates the effectiveness of a CRISPR-Cas13d-based approach in degrading viral RNA. crRNAs targeting conserved regions of NSP13, NSP14, and nucleocapsid transcripts achieved >99% silencing efficiency in human cells infected with various SARS-CoV-2 variants, including Delta and Omicron. Bioinformatics analysis showed the crRNAs could target almost 100% of the SARS-CoV family. The high specificity, efficiency, and rapid deployment potential of this system highlight its promise for antiviral drug development and protection against future variants.