This article describes the process of creation, structure and main activities of the Euroregion ―Upper Prut‖. Particular attention is paid to the peculiarities of Euroregions with the participation of administrative-territorial units of Ukraine, the Republic of Moldova and Romania, and the challenges of their effective operation. The activity of civil society institutions in a cross-border context, including their participation in projects within the framework of cross-border cooperation programs of the European Neighborhood and Partnership Instrument, is analyzed. The article represents the author’s proposals to improve the efficiency of the ―Upper Prut‖ Euroregion, presented to the participants of the international round table ―New European paradigms of cooperation and the potential of the ―Upper Prut‖ Euroregion‖, dedicated to the XXth anniversary of its formation, which was held on September 22, 2020.