We begin our reflection in this paper with the cursory observation that most of the major variants of the SARS CoV-2 virus were deciphered in the Global South, namely, alpha (China), beta and omicron (South Africa). This underappreciated fact demonstrates that independent capabilities in frontier sciences in the South contributed fundamentally to global efforts to minimise the human cost of the pandemic. However, while the more efficient vaccines primarily emerged from research and development (R&D)-based capabilities in the Global North, some novel vaccines, secondary innovation in the form of manufacturing and the innovative deployment of preventive measures were also salient in the Global South. Thus, rather than starting with the ‘deficit model of development’ that is implicit in several policy discourses on the Global South, we argue that innovation concepts should instead be anchored in the rich civilisational heritage of such societies themselves. Theoretical notions such as secondary innovation, which emerged from Chinese efforts at economic catch-up, endogenous development, which seeks to ground Africa’s advancement in its own historical antecedents, and grassroots innovation from the Indian subcontinent, guide our South–South dialogical exchange in this article. Consequently, we propose a contextually rooted conceptual framework on endogenous innovation that could better inform socially transformative efforts and highlight some implications for medicinal innovation and astronomy beyond COVID-19.