The Prairie Pothole Region (PPR) of north-central United States and south-central Canada supports greater than half of all breeding mallards (Anas platyrhynchos) annually counted in North America and is the focus of widespread conservation and research efforts. Allocation of conservation resources for this socioeconomically important population would benefit from an understanding of the nature of spatiotemporal variation in distribution of breeding mallards throughout the 850,000 km² landscape. We used mallard counts from the Waterfowl Breeding Population and Habitat Survey to test for spatial heterogeneity and identify high- and low-abundance regions of breeding mallards over a 50-year time series. We found strong annual spatial heterogeneity in all years: 90% of mallards counted annually were on an average of only 15% of surveyed segments. Using a local indicator of spatial autocorrelation, we found a relatively static distribution of low-count clusters in northern Montana, USA, and southern Alberta, Canada, and a dynamic distribution of high-count clusters throughout the study period. Distribution of high-count clusters shifted southeast from northwestern portions of the PPR in Alberta and western Saskatchewan, Canada, to North and South Dakota, USA, during the latter half of the study period. This spatial redistribution of core mallard breeding populations was likely driven by interactions between environmental variation that created favorable hydrological conditions for wetlands in the eastern PPR and dynamic land-use patterns related to upland cropping practices and government land-retirement programs. Our results highlight an opportunity for prioritizing relatively small regions within the PPR for allocation of wetland and grassland conservation for mallard populations. However, the extensive spatial heterogeneity in core distributions over our study period suggests such spatial prioritization will have to overcome challenges presented by dynamic land-use and climate patterns in the region, and thus merits additional monitoring and empirical research to anticipate future population distribution. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.