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Increasing prevalence of drug resistance makes the discovery of new NA inhibitors a high priority. Thirty-one triterpenoids from the medicinal mushroom <jats:italic>Ganoderma lingzhi<\/jats:italic> were analyzed in an <jats:italic>in vitro<\/jats:italic> NA inhibition assay, leading to the discovery of ganoderic acid T-Q and TR as two inhibitors of H5N1 and H1N1 NAs. Structure-activity relationship studies revealed that the corresponding triterpenoid structure is a potential scaffold for the design of NA inhibitors. Using these triterpenoids as probes we found, through further <jats:italic>in silico<\/jats:italic> docking and interaction analysis, that interactions with the amino-acid residues Arg292 and\/or Glu119 of NA are critical for the inhibition of H5N1 and H1N1. 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