Over time, the Danube has been a significant transportation hub, with a key role in developing a specific category of urban settlements: port cities. Several factors influenced the expansion of these cities, each with a different intensity and impact. Based on the historical context, port cities have experienced both times of evolution and periods of decline. Danube had major importance since the medieval period, but now they are facing economic difficulties. This paper aims to analyze two port cities in Romania by highlighting the role of ports and related activities in the economic development of cities. The port cities of Galați and Brăila were chosen as case studies; in these cities the role played by their ports as engines of development in the two cities was investigated. The study has three objectives: identify the factors that affected the development of port cities, pinpoint the present economic situation for the two selected case studies, and highlight future development prospects and opportunities by accessing European funding. The analysis revealed that after 1990, the change of political regime and transition to an open market economy affected the economic situation in the two cities studied. Nowadays, ports have much smaller importance in the economies of both studied cities. Few companies influence the port traffic: the Sidelurgic Plant and the Shipyard in the Port of Galați, and the Shipyard in the Port of Brăila. The analysis also identified examples of industrial units that depended on navigation, but were closed, reducing port traffic. However, Galați and Brăila did not take advantage of the opportunities offered by the Danube. These ports are part of the TEN-T network along the Rhine-Danube corridor. This network is an advantage because of the access provided to EU funding. Given the infrastructure problems of analyzed cities, the TEN-T network is an opportunity to improve connectivity. So far, the two cities in question have no airport or express road to link them, despite the existence of many plans drafted by local and central authorities. Another opportunity is represented by the Danube Bridge from Brăila, due in 2023. This bridge was supposed to play a significant role in the entire region by facilitating connections between Brăila, Galați, Tulcea, and Constanța.