Background The impacts of climate change on surface water, waterborne disease, and human health remain a growing area of concern, particularly in Africa, where diarrheal disease is one of the most important health threats to children under 5 years of age. Little is known about the role of surface water and annual flood dynamics (flood pulse) on waterborne disease and human health nor about the expected impact of climate change on surface-water-dependent populations. Methods and findings Using the Chobe River in northern Botswana, a flood pulse river—floodplain system, we applied multimodel inference approaches assessing the influence of river height, water quality (bimonthly counts of Escherichia coli and total suspended solids [TSS], 2011–2017), and meteorological variability on weekly diarrheal case reports among children under 5 presenting to health facilities (n = 10 health facilities, January 2007–June 2017). We assessed diarrheal cases by clinical characteristics and season across age groups using monthly outpatient data (January 1998–June 2017). A strong seasonal pattern was identified, with 2 outbreaks occurring regularly in the wet and dry seasons. The timing of outbreaks diverged from that at the level of the country, where surface water is largely absent. Across age groups, the number of diarrheal cases was greater, on average, during the dry season. Demographic and clinical characteristics varied by season, underscoring the importance of environmental drivers. In the wet season, rainfall (8-week lag) had a significant influence on under-5 diarrhea, with a 10-mm increase in rainfall associated with an estimated 6.5% rise in the number of cases. Rainfall, minimum temperature, and river height were predictive of E. coli concentration, and increases in E. coli in the river were positively associated with diarrheal cases. In the dry season, river height (1-week lag) and maximum temperature (1- and 4-week lag) were significantly associated with diarrheal cases. During this period, a 1-meter drop in river height corresponded to an estimated 16.7% and 16.1% increase in reported diarrhea with a 1- and 4-week lag, respectively. In this region, as floodwaters receded from the surrounding floodplains, TSS levels increased and were positively associated with diarrheal cases (0- and 3-week lag). Populations living in this region utilized improved water sources, suggesting that hydrological variability and rapid water quality shifts in surface waters may compromise water treatment processes. Limitations include the potential influence of health beliefs and health seeking behaviors on data obtained through passive surveillance. Conclusions In flood pulse river—floodplain systems, hydrology and water quality dynamics can be highly variable, potentially impacting conventional water treatment facilities and the production of safe drinking water. In Southern Africa, climate change is predicted to intensify hydrological variability and the frequency of extreme weather events, amplifying the public health threat of waterborne disease in surface-water-dependent populations. Water sector development should be prioritized with urgency, incorporating technologies that are robust to local environmental conditions and expected climate-driven impacts. In populations with high HIV burdens, expansion of diarrheal disease surveillance and intervention strategies may also be needed. As annual flood pulse processes are predominantly influenced by climate controls in distant regions, country-level data may be inadequate to refine predictions of climate—health interactions in these systems., Kathleen Alexander and colleagues determine the effects of river flood height, water quality and amount of suspended solids in river water in Botswana in response to climate change and weather variability and the resultant cases of diarrhoea in children under 5., Author summary Why was this study done? Diarrheal disease remains a persistent global health threat for children under 5 years of age, particularly in Africa. In river—floodplain systems, annual floods or flood pulses can occur, with extreme flooding and drought a common threat to local populations. We do not know how surface water dynamics influence diarrheal disease and human health or how climate change will affect populations dependent on surface water resources in these regions. What did the researchers do and find? We conducted a study on the Chobe River floodplain system in northern Botswana, a system that floods annually and is the source of drinking water for 8 villages included in the study. We evaluated diarrheal outbreak patterns in children under 5 years of age (weekly, 2007–2017) and individuals of all ages (monthly, 1998–2017) reporting diarrheal disease at government health facilities (n = 10). Using multimodel inference approaches, we assessed how meteorology, river height, and water quality characteristics (2011–2017) were associated with reports of diarrheal disease in children under 5 years of age. Across individuals of all ages, diarrheal outbreaks occurred regularly in the wet and dry seasons. Season had an important influence on the type of diarrhea and age group of the patient. Increases in diarrheal case reports were closely tied to meteorology, flood recession, and decreases in surface water quality, with the highest number of cases occurring in the dry season. What do these findings mean? In flood pulse river—floodplain systems, rapid changes in surface water quality may influence the ability of water treatment plants to provide safe drinking water. Climate change is expected to increase hydrological variability, further influencing the vulnerability of populations in this region. There is an urgent need to strengthen water infrastructure to address current and future environmental impacts that can influence the production of safe water. In populations with high HIV infection levels, public health focus may need to be extended to include other at-risk groups beyond children under five, such as HIV-infected individuals and others that may also be immunocompromised. As distant weather patterns influence local flood dynamics, use of country-level data may not be adequate to predict climate impacts on human health in these types of systems.