Globally, anthrax outbreaks pose a serious threat to people, livestock, and wildlife. Furthermore, environmental change can exacerbate these outbreak dynamics by altering the host–pathogen relationship. However, little is known about how the quantitative spatial dynamics of host movement and environmental change may affect the spread of Bacillus anthracis, the causative agent of anthrax. Here, we use real-time observations and high-resolution tracking data from a population of common hippopotamus (Hippopotamus amphibius) in Tanzania to explore the relationship between river hydrology, H. amphibius movement, and the spatiotemporal dynamics of an active anthrax outbreak. We found that extreme river drying, a consequence of anthropogenic disturbances to our study river, indirectly facilitated the spread of B. anthracis by modulating H. amphibius movements. Our findings reveal that anthrax spread upstream in the Great Ruaha River (~3.5 km over a 9-day period), which followed the movement patterns of infected H. amphibius, who moved upstream as the river dried in search of remaining aquatic refugia. These upstream movements can result in large aggregations of H. amphibius. However, despite these aggregations, the density of H. amphibius in river pools did not influence the number of B. anthracis-induced mortalities. Moreover, infection by B. anthracis did not appear to influence H. amphibius movement behaviors, which suggests that infected individuals can vector B. anthracis over large distances right up until their death. Finally, we show that contact rates between H. amphibius- and B. anthracis-infected river pools are highly variable and the frequency and duration of contacts could potentially increase the probability of mortality. While difficult to obtain, the quantitative insights that we gathered during a real-time anthrax outbreak are critical to better understand, predict, and manage future outbreaks.