Research in higher education often focuses on a single-level influence (local, national, regional, or global), while neglecting the interrelatedness of different levels and its impact on higher education. This study focuses on the supranational regional processes in higher education in the Global South and theorizes how higher education regionalization (HER) in the Global South is linked to coloniality in global higher education. Drawing from 15 semi-structured interviews with university leaders in East and Southeast Asia, this study examines why regional engagement is important and how it is different from global engagement with universities from other world regions. Findings suggest that HER in the Global South serves as a decolonial approach delegitimizing the enduring Western dominance in global higher education. Yet, enduring coloniality in global higher education, manifested in recolonization and self-colonization, poses threats to HER as a decolonial approach. Theoretically, the findings point out that HER in the Global South is linked to coloniality in global higher education, specifically through the complex entanglement of decolonization, recolonization, and self-colonization. In practice, this study urges higher education institutions in Global North and Global South to reflect on the current approach to internationalization that may reinforce coloniality in higher education.