This paper explores the intricate relationships among the evolution of the international political economy, the dynamics of business ecosystems, and the transformations in entrepreneurship within the European energy sector, with a specific emphasis on Greece, particularly the less developed region of Eastern Macedonia and Thrace. The aim is to understand how geopolitical, economic, and technological dynamics interact across macro-, meso-, and microlevels, especially within the context of the ongoing global energy transition. A multi-method approach is employed, including interviews with 16 experts, a survey of 89 energy firms, and eight in-depth interviews with microfirm owners. A key finding is that an integrated and evolutionary macro–meso–micro framework is essential for understanding and addressing the complex dynamics across various sectors, especially in the energy sector. The study highlights the need for targeted support for smaller firms through a restructured energy policy to foster local entrepreneurship and innovation. It further emphasizes that understanding the evolution of the global energy system and its components is crucial for addressing sustainability in environmental and socioeconomic terms, as the emerging model of energy production and consumption is directly tied to the reshaping of socioeconomic development models in the new globalization.