Pigeon circovirus (PiCV) is the most diagnosed virus in pigeons (Columba livia) and have been studied and reported globally. PiCV infections can lead to immunosuppression and pigeons infected with PiCV can result to lymphocyte apoptosis and atrophy of immune organs. Young pigeon disease syndrome (YPDS) is a complex disease and believed that PiCV could be one of the agents leading to this syndrome. An effective treatment regimen is needed to control the spread of PiCV in pigeons. In this study pigeon interferon alpha (PiIFN-α) was cloned and expressed and its antiviral effects were tested against fowl adenovirus type 4 (FAdV-4) in vitro and PiCV in vivo. No detectable levels of FAdV-4 viral genome in LMH cells stimulated with 300 μg/mL PiIFN-α were found. Additionally, PiIFN-α was stable at different temperature and pH for 4 h, and no reduction in antiviral activity was observed in untreated and treated cells. In pigeons naturally and experimentally infected by PiCV, no detectable levels of PiCV virus titers were found after treatment with PiIFN-α. Cytokine and ISG expression levels in liver and spleen samples were detected and IFN-γ and Mx1 genes were dominantly up-regulated following PiIFN-α treatment (p < 0.05). This study demonstrated that PiCV can be inhibited by administration of PiIFN-α and PiFN-α can be used as a therapeutic approach to prevent the spread of PiCV in pigeons.