Pleistocene climatic fluctuations had major impacts on desert biota in southwestern North America. During cooler and wetter periods, drought-adapted species were isolated into refugia, in contrast to expansion of their ranges during the massive aridification in the Holocene. Here, we use Melampodium leucanthum (Asteraceae), a species of the North American desert and semi-desert regions, to investigate the impact of major aridification in southwestern North America on phylogeography and evolution in a widespread and abundant drought-adapted plant species. The evidence for three separate Pleistocene refugia at different time levels suggests that this species responded to the Quaternary climatic oscillations in a cyclic manner. In the Holocene, once differentiated lineages came into secondary contact and intermixed, but these range expansions did not follow the eastwardly progressing aridification, but instead occurred independently out of separate Pleistocene refugia. As found in other desert biota, the Continental Divide has acted as a major migration barrier for M. leucanthum since the Pleistocene. Despite being geographically restricted to the eastern part of the species’ distribution, autotetraploids in M. leucanthum originated multiple times and do not form a genetically cohesive group.