Highly pathogenic avian influenza (HPAI) viruses of HxNy subtypes have dispersed across continents since 2005 through the movements of wild aquatic birds. This study synthesizes virological and ecological evidence and graphic visualizations (2005–2025) as to how avian influenza viruses (AIV) in aquatic avifauna linking the Caspian Basin, Eurasia and Africa have been transmitted and evolved. The initial westward incursion of virulent H5N1 in 2005–2006 established the Caspian Sea region as a dynamic nexus for viral dispersal. First identified in East Asia and transmitted to Siberian breeding sites, the virus reached the Caspian, then rapidly spread to Europe and Africa via migratory waterbirds. In subsequent years, H5N1 became enzootic in poultry in Egypt and elsewhere in Africa. In parallel, low-pathogenic H9N2 also became established in poultry systems in Egypt and the Maghreb and later contributed a PA gene segment to reassortant H5N1 in West Africa. A decade later, the Caspian flyways again conveyed emergent HxNy strains: in winter 2016–2017, H5N8 (clade 2.3.4.4b) caused mass die-offs of swans, ducks and other waterbirds in Iran and neighboring countries. Since 2020, this lineage has swept across Eurasia, Africa and the Americas in a panzootic, with the Caspian–Black Sea region at the convergence of intercontinental transmission flyways. Eurasian-origin viruses were carried into Africa by southward-moving waterbirds, and in turn African-origin gene segments reappeared in H5N1 strains that were transmitted north to Caspian breeding colonies in 2022. Bidirectional viral movement also has occurred between Western Europe and northern Eurasia. The aquatic bird flyway zones linking Africa and Eurasia can therefore be seen as a single global epidemiological system or enzootic continuum. Knowledge of the virological dynamics outlined in this study is important for surveillance, early warning and response to highly pathogenic avian influenza in both animal and public health at a time when the incidence of infections and threats of more virulent reassortants are assessed as critically high.