While influenza viruses are typically considered respiratory pathogens, the ocular system represents a secondary entry point for virus to establish a productive respiratory infection and the location for rare instances of virus-induced conjunctivitis. We used the ferret model to conduct a side-by-side comparison of virus infectivity, kinetics of viral replication, and induction of host responses following inoculation by either the intranasal or ocular routes with two viruses, A/Netherlands/230/03 (H7N7) and A/Panama/2007/99 (H3N2). We show that ocular inoculation resulted in delayed virus replication and reduced levels of proinflammatory cytokine and chemokine transcript in respiratory tract but not ocular tissues compared with intranasally inoculated animals. We identified numerous proinflammatory mediators with known roles in ocular disease elicited in ferret eye tissue following influenza virus infection. These findings provide a greater understanding of the modulation of host responses following different inoculation routes and underscore the risk associated with ocular exposure to influenza viruses. © 2013.