Closure of the Central American seaway was a local tectonic event with potentially global biotic and environmental repercussions. We report geochronological (six U/Pb LA‐ICP‐MS zircon ages) and geochemical (19 XRF and ICP‐MS analyses) data from the Isthmus of Panama that allow definition of a distinctive succession of plateau sequences to subduction‐related protoarc to arc volcaniclastic rocks intruded by Late Cretaceous to middle Eocene intermediate plutonic rocks (67.6 ± 1.4 Ma to 41.1 ± 0.7 Ma). Paleomagnetic analyses (24 sites, 192 cores) in this same belt reveal large counterclockwise vertical‐axis rotations (70.9° ± 6.7°), and moderate clockwise rotations (between 40° ± 4.1° and 56.2° ± 11.1°) on either side of an east‐west trending fault at the apex of the Isthmus (Rio Gatun Fault), consistent with Isthmus curvature. An Oligocene‐Miocene arc crosscuts the older, deformed and segmented arc sequences, and shows no significant vertical‐axis rotation or deformation. There are three main stages of deformation: 1) left‐lateral, strike‐slip offset of the arc (∼100 km), and counterclockwise vertical‐axis rotation of western arc segments between 38 and 28 Ma; 2) clockwise rotation of central arc segments between 28 and 25 Ma; and 3) orocline tightening after 25 Ma. When this reconstruction is placed in a global plate tectonic framework, and published exhumation data is added, the Central American seaway disappears at 15 Ma, suggesting that by the time of northern hemisphere glaciation, deep‐water circulation had long been severed in Central America.