A major topic of debate in earth science and climate science surrounds the timing of closure of the Central American Seaway. While it is clear that the gateway was closed by ca. 2.8 Ma, recent studies based on geological and marine molecular evidence have suggested an earlier closing time of early to mid-Miocene. In this study, we examined the influences of subduction and slab window formation on the time-varying paleoenvironments of the Isthmus of Panama region. We developed detailed reconstructions of the seafloor spreading history in the Panama Basin and incorporated previously published arc block rotations into a revised global plate model. Our reconstructions indicate that the Central American Seaway region has undergone multiple phases of slab window formation and migration, slab detachment, and flat slab subduction since the Oligocene, while kinematically mapped slab windows agree well with slab gaps imaged in seismic tomography. In particular, we found that from the early Miocene, when there is clear evidence for Isthmus of Panama emergence, the region was underlain by a slab window. During the late Miocene, when there is evidence for intermittent arc deepening, and decreased transcontinental migration, we found an increase in subducted slab volumes beneath the Panama arc. Numerical and analogue models and field observations argue that slab windows can induce >1 km of vertical uplift on the overriding plate. We therefore propose that this previously unexplored geodynamic mechanism can explain the variations in Isthmus of Panama emergence, and intermittent shallow-water connections, reconciling alternative lines of evidence for Central American Seaway closure.