There is little evidence on how the health impacts of drought vary spatially and temporally. With a focus on waterborne cryptosporidiosis, we identify spatio-temporal hotspots and by using interrupted time series analysis, evaluate the impact of Australia's Big Dry (2001–2009) in these disease clusters in the Murray Darling Drainage Basin. Analyses revealed a statistically significant spatio-temporal hotspot in the north of the Australian Capital Territory (ACT) and a hotspot in the north-eastern end of the basin in Queensland. After controlling for long-term trend and seasonality in cryptosporidiosis, interrupted time series analysis of reported cases in these hotspots indicated a statistically significant effect of the Big Dry. In both areas, the end of the Big Dry was associated with a lower rate of reported cryptosporidiosis; in the ACT, the estimated relative risk (RR) of reported cryptosporidiosis was 0.16 (95% confidence interval: 0.07; 0.33), with a greater decrease observed in Queensland of RR 0.42 (95% confidence interval: 0.19; 0.42). Although these data do not establish a causal association, this research highlights the potential for drought-related health risks.