Large European rivers are flowing through cultural landscapes. Their floodplains are usually narrowed, often keeping remnants of the natural vegetation in strips, with nodal extensions only at sites extremely prone to flooding. Sava River, the largest Danube tributary by its water flow, is still well preserved considering its free streaming from Slovenia, downstream borders between Croatia and Bosnia and Herzegovina, to its confluence in Belgrade, Serbia. The river corridor is functioning as a lifeline connecting different habitats. It is essential to wildlife migrations, seed transfers, and gene flow for both native and introduced species. Among the latter, many have been recognized to have invasive behavior. Invasive alien species (IAS), being recognized as the second most important cause of biodiversity loss on the global scale, are thus exploiting the river corridor, invading the natural habitats, and reducing the transnational river corridor connectivity. A platform for joint cross-border actions against IAS was developed in the Danube Transnational Project. Differences in legislative frameworks in the economies along the Sava River are still hampering its full implementation, giving the invasive species both time and space to further develop their populations, suppressing the native species, and increasing their influence in terms of ecological, social, and economic impacts.