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The CRISPR-Cas13 system has been proposed as an alternative treatment of viral infections. However, for this approach to be adopted as an antiviral, it must be optimized until levels of efficacy rival or exceed the performance of conventional approaches. To take steps toward this goal, we evaluated the influenza viral RNA degradation patterns resulting from the binding and enzymatic activity of mRNA-encoded LbuCas13a and two crRNAs from a prior study, targeting PB2 genomic and messenger RNA. We found that the genome targeting guide has the potential for significantly higher potency than originally detected, because degradation of the genomic RNA is not uniform across the PB2 segment, but it is augmented in proximity to the Cas13 binding site. The PB2 genome targeting guide exhibited high levels (>1 log) of RNA degradation when delivered 24 hours post-infection in vitro and maintained that level of degradation over time, with increasing multiplicity of infection (MOI), and across modern influenza H1N1 and H3N2 strains. Chemical modifications to guides with potent LbuCas13a function, resulted in nebulizer delivered efficacy (>1–2 log reduction in viral titer) in a hamster model of influenza (Influenza A/H1N1/California/04/09) infection given prophylactically or as a treatment (post-infection). Maximum efficacy was achieved with two doses, when administered both pre- and post-infection. This work provides evidence that mRNA-encoded Cas13a can effectively mitigate Influenza A infections opening the door to the development of a programmable approach to treating multiple respiratory infections. Author summary: For the CRISPR-Cas13 system to be adopted as an alternative treatment of viral infections, it must reach levels of efficacy that rival or exceed the performance of conventional approaches. We evaluated the degradation patterns resulting from the binding and enzymatic activity of mRNA-encoded LbuCas13a and two previously identified crRNAs, targeting conserved PB2 genomic and messenger RNA sequences. The genome targeting guide displayed higher potency than originally detected, because RNA degradation was augmented near the guide binding site, leading to 1-log of RNA degradation in vitro, which persisted over time, with increasing multiplicity of infection (MOI), and across modern influenza H1N1 and H3N2 strains. The addition of chemical modifications to the guide resulted in 1-2-log reduction in viral titer upon nebulizer delivery prophylactically or as a treatment in a hamster model of influenza. Maximum efficacy was achieved with two doses administered pre- and post-infection. [ABSTRACT FROM AUTHOR]