Influenza, a respiratory disease caused by influenza viruses, is still a worldwide threat with a high potential to cause a pandemic. Beside vaccination, only two classes of drugs are available for antiviral treatment against the pathogen. Here we show that CYSTUS052, a plant extract from a special variety of Cistus incanus that is rich in polymeric polyphenols, exhibits antiviral activity against a highly pathogenic avian influenza A virus (H7N7) in cell culture and in a mouse infection model. In vitro and in vivo treatment was performed with an aerosol formulation, because the bioavailability of high molecular weight polyphenols is poor. In MDCK cells, a 90% reduction of plaque numbers on cells pre-incubated with the plant extract was achieved. For in vivo experiments we used a novel monitoring system for influenza A virus-infected mice that allows measurement of body temperature and gross motor-activity of the animals. Mice treated with CYSTUS052 did not develop disease, showed neither differences in their body temperature nor differences in their gross motor-activity and exhibited no histological alterations of the bronchiolus epithelial cells.