This paper presents a methodological framework aiming to support the creation of a smart-tourism destination. Specifically, the study is realised in the frame of NEST, a European Union Interreg project aiming to create a smart-tourism destination in the Adriatic–Ionian area. Therefore, the study focuses on the southeastern Adriatic–Ionian area, as a portion of the European macro-region including the Italian regions of Molise and Apulia and the Balkan countries of Albania and Montenegro. This area presents a clear vocation for tourism, with a distinctive cultural heritage, attractive natural landscapes, and old culinary traditions offering a variety of eno-gastronomic and folk craft products. In the frame of the EU neighbour policies and in coherence with the objectives of the EU smart specialization strategy, several initiatives have been promoted for innovating the tourism offering in this area. Despite this, the full achievement of the creation of an Adriatic–Ionian smart destination calls for the adoption of a multidimensional strategy able to leverage knowledge-intensive dynamics of collaboration. This paper, therefore, aims to highlight the opportunities of adoptions and implications of this methodological framework for the cross-border marketing and management of the Adriatic–Ionian smart destination.