COVID-19 posed threats for health and well-being directly, but it also revealed and exacerbated social–ecological inequalities, worsening hunger and poverty for millions. For those focused on transforming complex and problematic system dynamics, the question was whether such devastation could create a formative moment in which transformative change could become possible. Our study examines the experiences of change agents in six African countries engaged in efforts to create or support transformative change processes. To better understand the relationship between crisis, agency, and transformation, we explored how they navigated their changed conditions and the responses to COVID-19. We document three impacts: economic impacts, hunger, and gender-based violence and we examine how they (re)shaped the opportunity contexts for change. Finally, we identify four kinds of uncertainties that emerged as a result of policy responses, including uncertainty about the: (1) robustness of preparing a system to sustain a transformative trajectory, (2) sequencing and scaling of changes within and across systems, (3) hesitancy and exhaustion effects, and (4) long-term effects of surveillance, and we describe the associated change agent strategies. We suggest these uncertainties represent new theoretical ground for future transformations research.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11625-023-01340-1.