Methods for the synthesis of fluorinated pyrido[1,2-a]benzimidazoles have been developed, and a series of such compounds has been obtained and studied for biological activity. In particular, 5,6-difluoro-2-cyanobenzimidazole (II) was synthesized for the first time using the reaction of 1,2-diamino-4,5-difluorobenzole (I) with cyanoacetic ether. Pyrido[1,2-a]benzimidazoles (III, IV) were obtained via condensation of benzimidazole II with diethylethoxymethylene malonate and ethyl acetoacetate. The synthesized pyrido[1,2-a]benzimidazoles (III–XIII) were subjected to screening on a culture of Vero cells for antiviral activity and cytotoxicity with respect to ortho-poxviruses that are pathogenic for humans.