Abstract Survival in hyperarid deserts is a major challenge for plant life, requiring the development of evolutionary strategies. The Atacama Desert presents harsh conditions such as limited rainfall, crusted soils, high soil salinity, high altitude, and intense solar radiation. These conditions, together with paleoclimatic variability since the past millions of years, have influenced the genetic structure and connectivity of plant populations, resulting in a diverse flora with high endemism. However, the diversification of most lineages appears to be relatively recent, in contrast to proposed age of the Atacama Desert and the onset, evolution and expansion of hyperarid conditions since the Late Oligocene and Early Miocene. A prominent exception is the Atacama paleoendemic Huidobria chilensis (Loasaceae), which is thought to be adapted to such conditions since the Eocene. Still, the environmental limits and thresholds for life in the Atacama remain poorly understood. To investigate the genetic structure in relation to the history of the Atacama Desert, we studied 186 individuals from 11 populations using genotyping-by-sequencing (GBS). Genome-wide single nucleotide polymorphisms (SNPs) were analyzed for population structure and genetic diversity. We identified three genetic clusters corresponding to geographic regions: the coastal region south of Tocopilla, the Coastal Cordillera around Chañaral, and the Copiapó watershed in the south. These clusters as well as genetic diversity were analyzed alongside rainfall, altitude, and landscape data. Although the genetic data generally supports isolation by distance as a major factor for genetic variation between populations, the study also reveals the influence of the topography on the distribution of H. chilensis and highlights the role of hydrologically connected watersheds and rivers in plant migration and colonization. This shapes the species’ evolutionary trajectory and genetic diversity. Understanding these patterns provides insights into the adaptation and survival strategies of plants in extreme desert environments such as the Atacama.