Curcumin derivatives have been shown to inhibitreplication of human infl uenza A viruses (IAVs). However, itis not clear whether curcumin and its derivatives can inhibitneuraminidase (NA) of influenza virus. In this study, ameaningful 3D quantitative structure–activity relationshipmodel (comparative molecular fi eld analysis R 2 = 0.997,q 2 = 0.527, s = 0.064, F = 282.663) was built to understandthe chemical–biological interactions between their activitiesand neuraminidase. Molecular docking was used to predictbinding models between curcumin derivatives and neuraminidase. Real-time polymerase chain reactions showed thatthe fi ve active curcumin derivatives might have direct eff ectson viral particle infectivity in H1N1-infected lung epithelial(MDCK) cells. Neuraminidase activation assay showed thatfi ve active curcumin derivatives decreased H1N1-inducedneuraminidase activation in MDCK cells. Indirect immunofluorescence assay indicated that two active curcuminderivatives (tetramethylcurcumin and curcumin) down-regulatedthe nucleoprotein expression. Curcumin inhibited IAVin vivo. The therapeutic mechanism of curcumin in the treatmentof infl uenza viral pneumonia is related to improvingthe immune function of infected mice and regulating secretionof tumor necrosis-α, interleukin-6, and interferon-γ. These results indicate that curcumin derivatives inhibit IAVby blocking neuraminidase in the cellular model and curcuminalso has anti-IAV activity in the animal model.