<p>This study explores the intersection of global megatrends and Education for Sustainable Development (ESD) in Cairo, Egypt. While research often addresses these intersections in developed contexts, this study fills a conceptual gap by theorizing how global drivers are negotiated within the resource and institutional constraints of the Global South. It assesses the extent to which current ESD practices in Egyptian higher education institutions (HEIs) contribute to addressing education-related megatrends. The study employed a multi-method approach, including a collaborative workshop (N = 22 from 10 HEIs) to quantitatively prioritize megatrends based on local awareness and relevance. This was complemented by in-depth interviews and field visits across five higher education institutions in Cairo to gain a deeper understanding of sustainability practices. Thematic analysis and comparative scoring were used to assess the alignment between institutional practices and prioritized megatrends and identify gaps and opportunities. The results reveal a significant disconnect between the high-priority global trends, such as digital transformation and artificial intelligence (AI), and their integration into institutional practices. Instead, the focus remains on traditional sustainability practices, such as renewable energy adoption, financial aid, and interdisciplinary curricula. To bridge divides in Egypt and beyond, the study proposes a reproducible, four-stage, contextually aligned framework that offers a transferable methodology for HEIs in resource-constrained environments to navigate systemic barriers and negotiate global sustainability imperatives. By prioritizing actions based on feasibility and impact, it provides actionable insights for aligning institutional practices with the Sustainable Development Goals and supports the integration of emergent technological and systemic changes into localized educational mandates.</p>