Long non-coding RNAs (LncRNAs) play pivotal regulatory roles in various biological processes, notably in immune regulation and viral infection. We previously identified the broad anti-influenza activity for LncRNA#61. Here, we further investigate the mechanism underlying its antiviral effect, both in vitro and in vivo. Using a lipid-nanoparticle-based delivery strategy, LncRNA#61 was successfully delivered into mice and effectively attenuated the replication and virulence of the highly pathogenic H5N1 influenza virus. Integrative transcriptomic analysis revealed that forced expression of LncRNA#61 markedly activated lipid metabolism, cell death, and Ragulator-Rag-mTORC1 pathways. Quantitative reverse transcription PCR analysis and a targeting metabolic assay further confirmed that LncRNA#61 is actively involved in regulating these pathways. Subsequent functional studies demonstrated that LncRNA#61 consistently enhances GSDMD-mediated pyroptosis both in murine LET-1 and canine MDCK cells. Notably, such pyroptosis was found to restrict H5N1 influenza virus replication. Intriguingly, ectopic expression of viral PA-X protein enhanced antiviral activity of LncRNA#61 both in vitro and in vivo. Mechanistically, PA-X interacts with LncRNA#61 and promotes LncRNA#61-mediated pyroptosis via a RagA-dependent reactive oxygen species pathway. Collectively, we here propose a novel model in which viral and host factors cooperate to activate a pro-death antiviral pathway. Our findings not only advance the fundamental knowledge of virus–host interactions but also cross-link cell death, innate immunity, and metabolic regulation, pinpointing novel therapeutic targets against influenza.