Education 4.0 (EDUC4) was driven by the onset of the Fourth Industrial Revolution (4IR) to meet labor market requirements resulting from learning that is customized, flexible, accessible, and skills-based. As the concept of EDUC4 develops popularity in the education and innovation research domains, various challenges about its implementation have emerged, especially in developing economies. Thus, there is a need to investigate the existing barriers to EDUC4 implementation. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, a systematic literature review of journal articles in the Scopus database was conducted. Of the 299 journal articles generated from the initial search on Scopus, 30 met the inclusion criteria and were included in the review. The content analysis yielded 12 barriers which include cybersecurity threat, costly, skills gap of human capital, apprehensive stakeholders, lack of training resources, lack of collaboration, knowledge gap for the customization of curriculum design, insufficient available technologies, health issues, time constraint for material preparation, complexity of learning platforms, and insufficient foundation of basic education. They were then associated with seven themes for better operationalization in Higher Education Institutions (HEIs): (1) human resources, (2) infrastructure, (3) financial, (4) linkages, (5) educational management, (6) learners, and (7) health and environment. Finally, a theoretical predictive model was constructed to present the causal relationships in modeling the problems associated with implementing EDUC4. The insights generated from this work offer both theoretical and practical perspectives for stakeholders of HEIs in the implementation of EDUC4 in developing economies.