<p>Contemporary global challenges, from climate crisis to geopolitical volatility and rapid technological disruption, have exposed the limitations of traditional globalization models. This paper introduces the concept of “Smart Sustainable Glocalization” as a paradigm for governance and innovation that strategically integrates global interconnectedness with local resilience, environmental sustainability, and digital transformation. Grounded on the Quintuple Innovation Helix (QIH) framework (Carayannis, 2012–2025; Carayannis et al., TFSC, 2025), which integrates academia, industry, government, civil society, and the environment, and empowered by artificial intelligence (AI) as a cross-cutting enabler. This model redefines how societies can align global commitments with regional sustainable growth and supports their interdependence. Drawing upon the literature on reflexive modernization, smart specialization, sustainability transitions, and digital advancements, this paper examines the importance of strengthening local regions, to enhanced reflexivity, evidence-based policy-making and multi-level coordination over helix actors. Methodologically, this study synthesizes theoretical frameworks and policy evidence from the United Nations, European Union, and global innovation systems. The findings indicate that “Smart Sustainable Glocalization”, which can be realized through the systematic and innovative use of the Quintuple innovation helix model, Smart Sustainable Specialisation Strategies S4 and S4 + and AR2IA/S4 framework and digital developments, offers a viable pathway for navigating into today’s volatile, uncertain, complex, and ambiguous world dynamics by promoting resilience, adaptive innovation, inclusive governance, and environmental stewardship. The paper concludes by suggesting policy implications for governments, industry, academia, civil society, and international institutions, highlighting the need for AI governance, local capacity-building, and globally aligned sustainability strategies.</p>