European Union (EU) policy encourages the development of a blue economy (BE) by unlocking the full economic potential of oceans, seas, lakes, rivers and other water resources, especially in member countries in which it represents a low contribution to the national economy (under 1%). However, climate change represents a main barrier to fully realizing a BE. Enabling conditions that will support the sustainable development of a BE and increase its climate resiliency must be promoted. Romania has high potential to contribute to the development of the EU BE due to its geographic characteristics, namely the presence of the Danube Delta–Black Sea macrosystem, which is part of the Romanian Lower Danube Euroregion (RLDE). Aquatic living resources represent a sector which can significantly contribute to the growth of the BE in the RLDE, a situation which imposes restrictions for both halting biodiversity loss and maintaining the proper conditions to maximize the benefits of the existing macrosystem. It is known that climate change causes water quality problems, accentuates water level fluctuations and loss of biodiversity and induces the destruction of habitats, which eventually leads to fish stock depletion. This paper aims to develop an analytical framework based on multiple linear predictive and forecast models that offers cost-efficient tools for the monitoring and control of water quality, fish stock dynamics and biodiversity in order to strengthen the resilience and adaptive capacity of the BE of the RLDE in the context of climate change. The following water-dependent variables were considered: total nitrogen (TN); total phosphorus (TP); dissolved oxygen (DO); pH; water temperature (wt); and water level, all of which were measured based on a series of 26 physicochemical indicators associated with 4 sampling areas within the RLDE (Brăila, Galați, Tulcea and Sulina counties). Predictive models based on fish species catches associated with the Galati County Danube River Basin segment and the "Danube Delta” Biosphere Reserve Administration territory were included in the analytical framework to establish an efficient tool for monitoring fish stock dynamics and structures as well as identify methods of controlling fish biodiversity in the RLDE to enhance the sustainable development and resilience of the already-existing BE and its expansion (blue growth) in the context of aquatic environment climate variation. The study area reflects the integrated approach of the emerging BE, focused on the ocean, seas, lakes and rivers according to the United Nations Agenda. The results emphasized the vulnerability of the RLDE to climate change, a situation revealed by the water level, air temperature and water quality parameter trend lines and forecast models. Considering the sampling design applied within the RLDE, it can be stated that the Tulcea county Danube sector was less affected by climate change compared with the Galați county sector as confirmed by water TN and TP forecast analysis, which revealed higher increasing trends in Galați compared with Tulcea. The fish stock biodiversity was proven to be affected by global warming within the RLDE, since peaceful species had a higher upward trend compared with predatory species. Water level and air temperature forecasting analysis proved to be an important tool for climate change monitoring in the study area. The resulting analytical framework confirmed that time series methods could be used together with machine learning prediction methods to highlight their synergetic abilities for monitoring and predicting the impact of climate change on the marine living resources of the BE sector within the RLDE. The forecasting models developed in the present study were meant to be used as methods of revealing future information, making it possible for decision makers to adopt proper management solutions to prevent or limit the negative impacts of climate change on the BE. Through the identified independent variables, prediction models offer a solution for managing the dependent variables and the possibility of performing less cost-demanding aquatic environment monitoring activities.