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This chapter theoretically examined coronavirus (COVID-19) and entrepreneurship in Africa. Also, the challenges and opportunities of small and medium enterprises (SMEs) innovation were assessed. The researchers adopted a qualitative method to review secondary data, information from previous kinds of literature including pertinent internet sources and working papers. Similarly, the chapter considered an innovative-based perspective of entrepreneurship and explicates the emerging opportunities created by COVID-19. The chapter also analyzed the COVID-19 and its effect on entrepreneurship in Africa by identifying and discussing existing challenges caused by the pandemic. Furthermore, some information about the nature of COVID-19 and its effects in Africa were adequately evaluated. Gleaned evidence from literature revealed that there is a possibility that the unpremeditated damage to entrepreneurship in Africa as caused by the COVID-19 could be persistent. The chapter also showed that the emergence of the COVID-19 has threatened the survival of businesses especially SMEs, thereby increasing the level of unemployment across the African continent and has generated critical challenges for entrepreneurship development. Finally, the chapter will add to the evolving challenges and opportunities of entrepreneurship in Africa. However, entrepreneurs can build on the strengths of innovative activities to develop a survival mindset, develop financial resilience and adjust business archetypes to the realities of COVID-19 and post-COVID-19 era which in the short and long term can accentuate entrepreneurship development within African continent.