Baicalin was identified as a neuraminidase (NA)inhibitor displaying anti-influenza A virus (IAV) activity. However, its poor solubility in saline has limited its use inthe clinic. We generated sodium baicalin and showed that itexhibited greatly increased solubility in saline. Its efficacyagainst oseltamivir-resistant mutant A/FM/1/47-H275Y(H1N1-H275Y) was evaluated in vitro and in vivo. Resultsshowed that 10 lM of sodium baicalin inhibited A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2) and H1N1-H275Y inMDCK cells in a dose-dependent manner, with inhibitoryrates of 83.9, 75.9 and 47.7%, respectively. Intravenousadministration of sodium baicalin at 100 mg/kg/d enabledthe survival of 20% of H1N1-H275Y-infected mice. Thetreatment alleviated body weight loss and lung injury. Moreover, sodium baicalin exerted a clear inhibitory effecton NAs. The IC50 values of sodium baicalin against H1N1-H275Y and cells-expressing A/Anhui/1/2013-R294K(H7N9-R294K) NA protein (N9-R294K) were 214.4 lMand 216.3 lM. Direct interactions between sodium baicalinand NA were observed, and we simulated the interactionsof sodium baicalin with N9-R294K and N9 near the activesites of OC-N9-R294K and OC-N9. The residues responsiblefor the sodium baicalin-N9-R294K and sodiumbaicalin-N9 interactions were the same, confirming thatsodium baicalin exerts effects on wild-type and oseltamivir-resistant viral strains.