Over the twentieth century, the concept of the natural experiment has become increasingly prominent across a variety of disciplines, albeit most consequentially in epidemiology and public health. Drawing on an analysis of the scientific and medical literature, we explore the social life of the natural experiment, tracing its changing use, meaning and uptake to better understand the work done by the concept. We demonstrate how the natural experiment became central to the identity of post-war epidemiology as the discipline professionalised, turned its attention to the prevention of chronic disease and took centre stage in the field of public health. We then turn to its growing significance amid the rise of evidence-based medicine, and the new meanings natural experiments came to take on in the context of concerns about policy and evidence. Finally, we turn to the newest iteration of the natural experiment in the COVID-19 era, which saw an explosion of studies drawing on the term, albeit in ways that reveal more about the underlying politics of health than the method itself. Throughout, we illustrate that the concept of the natural experiment has always been fundamentally social and political and tied to disciplinary claims-making about evidence and what should count as such.