Influenza A virus (IAV) is found in a range of different hosts but mainly circulates in waterfowl, shorebirds, and gulls, which constitute the major natural reservoir. However, mammalian species can also harbour infection. IAV is regularly detected in marine mammals and have been the source of multiple epizootics over the past decades. Still, it remains unclear if infections are spill-over events, or if marine mammals serve as a reservoir host where IAV can be maintained, circulate, and undergo reassortment and/or mammalian adaptation. Little is known about the mechanisms of cross-species transmission and pathogenicity of some IAV strains. Harbour seals (Phoca vitulina) account for 50% of reported IAV infections in marine mammals, they host the most diverse assembly of IAV strains, and is the only species in which IAV is pathogenic with six epizootics since the late 1970s. Here we use genomic IAV data to track the spatiotemporal origin, investigate transmission routes of pathogenic IAV strains, and identify mutations in the IAV genome that may be associated with marine mammal adaptation and pathogenicity. Our study reveal that pathogenic IAV strains are of avian origin with multiple and rapid genetic changes associated with the cross-species transmission. IAV infections in marine mammals typically result from spill-over events from birds. Harbour seals appear to be a dead-end host and given the frequent occurrence of epizootics in harbour seals, but not in other marine mammals, it seems that IAV pathogenicity in marine mammals may be more related to host susceptibility rather than viral adaptation.