<p>Greece, following a prolonged socio-economic crisis, has shown strong regional disparities, characterized by population decline and multi-level socio-economic vulnerabilities. Such a situation constitutes a significant challenge for creating conditions for Sustainable Development. The purpose of this study is to investigate and examine the relationship between population change and key socio-economic indicators through a diagnostic approach. The study concerns all Greek regions and at the same time seeks to integrate the analysis, within the framework of a broader political dialogue, of sustainable transition through the Bioeconomy and Circular Economy. The data used in the analysis are secondary at the NUTS II level, from the most official statistical sources in the European Union. In addition, descriptive statistics and Pearson correlation analysis are the main tools of empirical analysis and investigation of the relationships between population change and income levels, poverty rates and long-term unemployment. The findings present a series of significant statistical relationships between demographic change and socio-economic conditions. These results reveal distinct patterns of spatial inequality, while at the same time highlighting regions with increased exposure to risks. It is important to mention that both the policies and strategies of the Bioeconomy and Circular Economy have no empirical application in this study. However, the article includes a systematic review of the international literature, aiming to investigate whether the tools of the Bioeconomy and Circular Economy can cope with addressing structural challenges in economically vulnerable regions. Through the findings of the article, important cognitive elements of a socio-economic dimension are provided, while highlighting the need for future empirical investigation. The vision is clear and concerns the support of analyses and political practices that aim at Sustainable Development in the Greek regions.</p>