Infections with influenza A viruses are still a major threat to humans and several animal species. The occurrence of highly pathogenic avian influenza viruses capable of infecting and killing humans highlights the urgency for a new and efficient strategy for the treatment of diseases caused by the virus. Andrographolide and its derivatives have been widely used for treating respiratory infections in China for decades. We have recently synthesized new andrographolide derivatives and found that some of the compounds including 14-α-lipoyl andrographolide (AL-1) have significant activity against bacterial infections with an unique mechanism of action. We report here the antiviral activity of AL-1 and other andrographolide drugs. AL-1 showed significant activity against influenza A viruses including the H5N1 avian influenza virus. The administration of AL-1 by oral gavage to mice infected with avian influenza A/Chicken/Guangdong /96 (H9N2), A/Duck/Guangdong/99 (H5N1), and human influenza A/PR/8/34 (H1N1) viruses greatly reduced the death rate, prolonged life, inhibited lung consolidation, and reduced viral titers in the lung. The most effective dosage of AL-1 in these studies ranged from 100 to 200 mg/kg/d, when administered twice daily for 7 d beginning 24 h before viral exposure. The LD50 of AL-1 was 1243 mg/kg/d. AL-1 was effective against avian influenza A (H9N2 and H5N1) and human influenza A H1N1 viruses in vitro, with the 50% effective concentrations ranging from 7.2 to 15.2 μM and the selective indexes ranging from 51 to 109. Significant inhibition of viral adsorption onto red blood cells with minimum inhibitory concentrations ranging from 5.3 to 16.8 mM suggested that AL-1 was capable of directly interfering with viral hemagglutinin to block binding to cellular receptors. With potent antiviral activity and a potentially new mechanism of action, AL-1 may warrant further evaluation as a possible therapy for influenza.