Nyssa (Nyssaceae, Cornales) represents a classical example of the well‐known eastern Asian‐eastern North American floristic disjunction. The genus consists of three species in eastern Asia, four species in eastern North America, and one species in Central America. Species of the genus are ecologically important trees in eastern North American and eastern Asian forests. The distribution of living species and a rich fossil record of the genus make it an excellent model for understanding the origin and evolution of the eastern Asian‐eastern North American floristic disjunction. However, despite the small number of species, relationships within the genus have remained unclear and have not been elucidated using a molecular approach. Here we integrate data from 48 nuclear genes, fossils, morphology, and ecological niche to resolve species relationships, elucidate its biogeographic history, and investigate the evolution of morphology and ecological niches, with the goal toward a better understanding of the well‐known EA‐ENA floristic disjunction. Results showed the Central American (CAM) N. talamancana was sister to the remaining species, which were divided among three, rapidly diversified subclades. Estimated divergence times and biogeographic history suggested Nyssa had an ancestral range in Eurasia and western North America in the late Paleocene. The rapid diversification occurred in the early Eocene, followed by multiple dispersals between and within the Erasian and North American continents. The genus experienced two major episodes of extinction in the early Oligocene and end of Neogene, respectively. The Central American N. talamancana represents a relic lineage of the boreotropical flora in the Paleocene/Eocene boundary that once diversified in western North America. The results supported the importance of both the North Atlantic land bridge and the Bering land bridge (BLB) for the Paleogene dispersals of Nyssa and the BLB for the Neogene dispersals and the role of Central America as refugia of the Paleogene flora. The total‐evidence based dated phylogeny suggested that the pattern of macroevolution of Nyssa coincided with paleoclimatic changes. We found a number of evolutionary changes in morphology (including wood anatomy and leaf traits) and ecological niches (precipitation and temperature) between the EA‐ENA disjunct, supporting ecological selection driving trait evolutions following geographic isolation. We also demonstrated challenges in phylogenomic studies of lineages with rapid diversification histories. The concatenation of gene data can lead to inference of strongly supported relationships incongruent with the species tree. However, conflicts in gene genealogies did not seem to impose a strong effect on divergence time dating in our case. Furthermore, we demonstrated that rapid diversification events may not be recovered in divergence time dating analysis using BEAST if critical fossil constraints of the relevant nodes are not available. Our study provides an example of complex bi‐directional exchanges of plants between Eurasia and North America in the Paleogene but “out of Asia” migrations in the Neogene to explain the present disjunct distribution of Nyssa in EA and ENA.