In recent years, zoonotic strains of avian influenza have emerged as a significant global health concern, with fears that these viruses could develop sustained human-to-human transmission with potentially devastating consequences. These strains normally circulate in waterfowl, but under certain circumstances are able to cross the species barrier into mammals, making how these viruses interact with their hosts critical to combatting these zoonotic events. While much work has gone into understanding the human response to influenza viruses, little work has been done in the ferret model of mammalian influenza, in order to compare to the regular avian hosts. Thus, we investigated the populations of immune cells in the blood and tissues of both ferrets and chickens from animal trials, using novel flow cytometry panels, to assess the impact of avian influenza virus infection on lymphocyte subsets. Our data has elucidated a number of important phenotypic changes in immune subsets in response to infection with avian influenza strains, which may suggest differing mechanisms of disease progression across the different hosts. Highly pathogenic strains such as H5N1 and H5N6 cause a depletion of CD8+ lymphocyte populations in chicken spleen, whilst in ferrets these lymphocytes to appear to increase in the periphery. Similarly, for the low pathogenicity H7N9 strain which causes severe disease in mammals, CD8+ T cells were maintained in the spleen but showed an influx into the lung following infection in ferrets, suggesting mobility of immune cells to counter infection. Moreover, in animals which survived the virus challenge greater numbers activated macrophages showing increased GL7 and MHCII expression appear to correlate to less severe outcomes. These results, coupled with investigations into other immune correlates, support the idea that the severe clinical signs of avian influenza viruses are multifaceted in origin and differ across species. These studies give insight into the potential mechanisms allowing these viruses to cause severe illness across species, and may help better our understanding of emerging zoonotic and pandemic influenza threats.