Cardiac glycosides (CG) are used primarily for cardiac failure and have been reported to have other effects, including inhibition of viral replication. Here we set out to study mechanisms by which CG as inhibitors of the Na,K-ATPase, decrease influenza A virus (IAV) replication in the lungs. We found that CG inhibit influenza virus replication in alveolar epithelial cells by decreasing intracellular potassium which in turn inhibits protein translation, independently of viral entry, mRNA transcription, and protein degradation. These effects were independent of the Src signaling pathway and intracellular calcium concentration changes. We found that short-term treatment with ouabain prevented IAV replication without cytotoxicity. Rodents express a Na,K-ATPase α1 resistant to GC. Thus, we utilized Na,K-ATPase α1 sensitive mice, infected them with high doses of influenza virus and observed a modest survival benefit when treated with ouabain. In summary, we provide evidence that the inhibition of the Na,K-ATPase by CG decreases influenza A viral replication by modulating the cell protein translational machinery and results in a modest survival benefit in mice.