Background: The Fourth Industrial Revolution (4IR) presents a number of implications for both the public and private sectors. An important feature of the 4IR is enhancing the sustainability of businesses through innovation.Aim: This article examines the government’s entrepreneurial role in promoting innovation-led entrepreneurial ecosystems (EEs).Setting: Through a comparative approach, the research presented in this article investigates the role of government in promoting innovation-led EEs, in a top-performing EE, namely Silicon Valley and South Africa.Methods: A qualitative research design is adopted, and unobtrusive research methods are used for the conceptual, contextual and comparative analysis of authoritative literature and secondary data. A best practice case of Silicon Valley is used to analyse factors influencing innovation-led EE development in South Africa.Results: Challenges currently influencing the growth and sustainability of entrepreneurship in South Africa are identified. These challenges include 4IR readiness, policy implementation and the impact of the coronavirus disease 2019 (COVID-19) pandemic. The findings suggest that governments should play an important role in shaping innovation-led EE policy implementation.Conclusion: The article concludes by proposing a conceptual framework to aid managerial and policy guidance for the development of innovation-led EEs.Contribution: The findings of this article will be useful to guide managerial and policy guidance on the role of government in shaping innovation-led EE policy implementation.