This paper investigates the impact of demographic changes on regional specialisation across Greek NUTS2 regions from 2001 to 2021. It explores the relationship between age-specific variations in the economically active population and gross value added (GVA) across different economic sectors. Using demographic and GVA data alongside spatial analysis techniques such as spatial regression models, median Local Moran’s I, and location quotient, the study identifies spatial autocorrelation patterns. Findings reveal strong correlations between the economically active population and GVA, highlighting demographic factors’ crucial role in regional economic performance. Over the period 2001 to 2021, the 15–24 and 25–34 age groups generally experienced declining growth rates in total, male, and female economically active populations, while the 45–54 and 55–64 age groups saw increases. Regions adjacent to those with higher economically active populations showed high–high clustering. Especially, Attiki and Kentriki Makedonia, the two metropolitan regions of Greece, influence neighbouring regions through economic spillover effects, fostering economic sector clustering and emphasising regional specialisation. These findings highlight the complex interplay between demographic shifts and regional economic outcomes, noting spatial disparities and the need for targeted policy interventions. The study provides empirical evidence demonstrating how demographic changes influence regional economic development across different regions.