<b><i>Background:</i></b> The zoonotic transmission of highly pathogenic avian influenza viruses and the global pandemic of H1N1 influenza in 2009 signified the need for a wider coverage of therapeutic options for the control of influenza. <b><i>Methods:</i></b> An in-house compound library was screened using a cytopathic effect inhibition assay. Selected hits were then tested in vivo and used as a core skeleton for derivative synthesis. <b><i>Results:</i></b> The hit compound (BMD-2601505) was effective [50% effective concentration (EC₅₀) of 60-70 μ<smlcap>M</smlcap>] in reducing the death rate of cells infected with human influenza A and B viruses as well as avian influenza A virus. Furthermore, BMD-2601505 reduced the weight loss and increased the survival after lethal infection. The compound was further modified to enhance its antiviral potency. Results show that one derivative with bromobenzene moiety was most effective (EC₅₀ of 22-37 μ<smlcap>M</smlcap>) against the influenza viruses tested. <b><i>Conclusion:</i></b> We identified a small benzamide compound exhibiting antiviral activity against influenza viruses. The results warrant further evaluation of antiviral activities against drug-resistant influenza isolates.