The Southern Appalachian region of North America harbors exceptionally high levels of endemic woody plant diversity, including several polyploids of Vaccinium sect. Cyanococcus (the true blueberries). Contrasting hypotheses for the evolutionary origins of some of these polyploids have been proposed but undermined by taxonomic uncertainty. We integrated genomic data, flow cytometry analysis, and morphological investigation to infer the origin and evolutionary history of the endemic Southern Appalachian polyploid blueberries recognized here and further circumscribed as V. constablei (6x), V. hirsutum (4x), and V. simulatum (4x). Phylogenomic analyses suggest independent origins for these three species, most likely a result of ancient autopolyploidy. Vaccinium simulatum is sister to the extant diploid V. pallidum, a likely progenitor, whereas V. hirsutum appears to be derived from a diploid V. myrtilloides-like ancestor. The origin of V. constablei remains cryptic but this species is likely an early-branching lineage without clear morphological connections to extant species within the northern clade of V. sect. Cyanococcus. With this knowledge, combined with intensive field investigation and herbarium study, we provide a taxonomic revision of the endemic polyploid Southern Appalachian members of the section. The revision includes descriptions, ecological information, county-level distribution maps, and representative specimens cited, along with a key to all members of the section that occur in the Southern Appalachians. We also provide lectotypes for V. carolinianum and V. constablei.