The Danube Delta is one of Earth’s biodiversity hotspots and includes many endemic, rare, and important species of both major conservation and economic value. This unique complex of ecosystems also plays a key role for Danube River and Black Sea fish fauna through its role as a natural safe buffer, shelter, feeding, reproduction, and smooth transitional area for a large number of fish species. Climate change is inducing a progressive sea level rise in the Black Sea, a fact that is expected to impact the delta’s key complex and dynamic habitats, biocoenoses, and associated biota, and last but not least the key taxonomic group, namely, fish. Around one-third of the fish species of this delta will be greatly affected, sometimes negatively, by this climate change scenario, another one-third to a lesser extent, and the final one-third not at all. The ecological positive feedback of fish can stimulate environmental change and is expected to be responsible for changes within Danube Delta ecosystems, and also for the near Danube River and Black Sea diverse matrix of aquatic and semi-aquatic ecosystems. Sea level rise in the Black Sea is considered to have been one of the main stress factors of the Danube Delta fish fauna in the past, and is likely to be the case in the future. In this spatio-temporal dynamic context, for the fish species under threat and risk, in situ-adapted management measures are highly required. The current work brings for the first time such a prospective knowledge about the potential impact on Danube River–Danube Delta–Black Sea coast fish diversity in the potential climate change–sea level rise scenario.