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Globally, digital disruption has accelerated in the last few years. It is argued that this technological revolution would fundamentally alter our interactions with one another, our work, and our lives. The Fourth Industrial Revolution (4IR) can blur the boundaries between the physical and biological worlds. Although the extent of the effect is unclear, many anticipate massive changes in the economic and educational spheres. Given the close relationship between the economy and the drivers of entrepreneurship in universities, the survival of entrepreneurial universities remains contingent on the influence and preparedness of the 4IR. This review aimed to ascertain South African entrepreneurial universities’ readiness for the 4IR. Systematic literature analysis was adopted for this study; it draws on journal articles, books as wells as online publications relating to disruptive innovation, entrepreneurial universities, and 4IR. The paper argues that there is a need for a radical overhaul of the current curriculum, as retraining lecturers to prepare for 4IR disruptions.