In 2018, the World Health Organization (WHO) announced the addition of Disease X, a hypothetical infectious threat, to its blueprint list of priority diseases. In the construction of discourse that circulated following this announcement, conceptions of Disease X intersected with representations of Africa. In our article, we share a broad strokes analysis of internet narratives about Disease X and Africa in the six months before the onset of the COVID-19 pandemic (July–December 2019) and during its first six months (January–June 2020). Our analysis focuses on how the scientific concept of Disease X was applied by ‘non-experts’ to make meaning from risk, uncertainty, and response. These non-experts drew in parallel upon more general representations of power, fear, and danger. This research is particularly relevant at the time of writing, as online narratives about COVID-19 vaccination are shaping vaccine anxiety throughout the world by drawing upon similar conceptions of agency and inequality. Because Disease X in Africa still looms as a perceived future threat, considering the narratives presented in this paper can provide insight into how people create meaning when faced with a scientific concept, a global health crisis, and the idea that there are other crises yet to come.