The rapid emergence of novel virulent strains and the increasing zoonotic spillover of avian influenza viruses pose significant threats to global health and cause substantial economic losses in the livestock industry. Complicating these challenges is the development of escape mutants that undermine current intervention strategies. This study investigates the potential of the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas13 system, an RNA-guided RNA-degrading tool, as an effective antiviral strategy. We evaluated five CRISPR/Cas13 variants—LwaCas13a, PspCas13b, HF-Cas13d, Cas13e3, and HF-Cas13x—by assessing their target-specific and collateral activities using fluorescence reporters in chicken fibroblast cells. Among these, HF-Cas13d emerged as the most effective, achieving over 90% target-specific knockdown without compromising cell viability. However, HF-Cas13d also displayed collateral activity on non-target fluorescence reporters. Transgenic HF-Cas13d cells expressing influenza-specific guide RNAs successfully reduced influenza viral load by up to two logarithmic scales when targeting a single viral gene. While these findings highlight the promise of CRISPR/Cas13 as an antiviral strategy, further studies involving multiplexed guide RNAs and testing against highly pathogenic avian influenza strains are necessary to fully realize its potential.