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Highlights • Imidazole was found to be the potential inhibitor of Newcastle disease virus (NDV) infection. • The imidazole derivative was found equally effective to reduce NDV infection in chicken. • The imidazole and its derivative specific activities could be due to modulation of type I interferon. Abstract Despite recent progress in vaccination options, Newcastle disease virus (NDV) stands a severe global epidemic and economic burden. It is difficult to control NDV with vaccination alone due to its evolving genetic variability; therefore, an effective therapeutic must target to resist its replication and further evolution. Drug repurposing is a practical and economical method to develop therapeutics against pathogenic organisms. Applying the knowledge of the broadly used antimicrobial activity of imidazole and its derivatives, we performed repurposing-based design of therapeutics to induce protection against NDV. We checked the ability of the compound at sub-lethal doses to reduce NDV replication in vitro , in ovo and in vivo. Chickens treated with the repurposed drug produced antiviral type I interferon and showed no shedding of the virus. Successful designing of novel NDV drug, in this study empirically demonstrates the principle that repurposing can be used for developing antiviral therapeutics. [ABSTRACT FROM AUTHOR]