To date, the relatively scarce large-scale phylogeographic studies of eastern North American flora have primarily focused on canopy trees with wind-dispersed seeds. Given the varied topography of eastern North America, possible locations of Pleistocene refugia, and differential rates of post-glacial migration from those refugia, overall phylogeographic patterns are less well-studied than other temperate regions around the world and appear to be largely species-dependent. It had also been hypothesized that human-mediated dispersal of useful plant species may have affected the rate of post-LGM migration and range expansion of some valued species during the Holocene epoch. It seems timely to conduct a regional phylogeographic study on patterns of genetic diversity of the highly clonal, mammal-dispersed, useful understory tree species, Asimina triloba. The goals of this work are to 1) estimates levels and patterns of genetic diversity and structure across the species’ range, 2) infer locations of Pleistocene refugia, 3) compare patterns of genetic diversity of putative anthropogenic populations with that of wild populations, and 4) investigate levels of clonality within populations across the species range. For a tree species, genetic diversity and structure among A. triloba populations was moderately high, though isolation-by-distance was not significant. The Appalachian Mountains appear to have acted as a barrier to dispersal during northward post-glacial migration and range expansion. Another east-west genetic discontinuity was detected on either side of the Tombigbee River in Alabama. These results are consistent with the inference by ecological niche modeling of two principal Pleistocene refugia, separated by peninsular Florida. Most measures indicated that genetic diversity was significantly lower in putative anthropogenic populations than wild populations, with the exception of heterozygosity, which was higher in anthropogenic populations. This work represents the first genetic evidence for human manipulation of a valued eastern North American tree species. Clonality was observed to vary greatly across the range, with more cloning on the edges of the species range and high heterozygosity of dominant clones. Spatial genetic structure within populations appeared to be strongly linked to clonal growth. This study represents the first regional phylogeographic study on a mammal-dispersed understory tree in eastern North America.