AbstractGeographically, widespread Neotropical fish lineages offer opportunities to reconstruct historical biogeography patterns and infer processes leading to modern ichthyological diversity and distribution. The characiform family Prochilodontidae is well suited for such reconstruction because their migrations limit population substructure within river systems. Therefore, their biogeographic history should match closely the history of connectivity among Neotropical river basins. Here, we combine a time‐calibrated phylogeny with biogeographic model testing to recover the history of this family's diversification. Results support the Miocene rise of the Andean Eastern Cordillera as a dispersal barrier, but also indicate a much earlier Eocene origin of the trans‐Andean genus Ichthyoelephas. Despite the early origin of the family and its three constituent genera, most prochilodontid lineages originated during the Miocene in Greater Amazonia, likely due to drainage reorganizations caused by Andean uplift. Subsequent speciation appears linked to interbasin exchanges and expansions of Amazonian lineages into Brazilian coastal systems. The modern richness of Prochilodus in easterly drainages appears to be relatively young, with only Prochilodus vimboides likely reaching that region prior to the late Miocene. The rise of the Vaupes Arch coincides with two splits between Orinocoan and Amazonian lineages circa 9 million years ago (Ma). However, two instances of later dispersal between these drainages reveal the permeability of the Vaupes Arch, suggesting that it may promote periodic speciation. This study illustrates how model‐based biogeographic studies of widespread groups can reconstruct historic paths of dispersal and help reveal how landscape evolution promoted modern diversity patterns.