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El primer esbozo del Istmo de Panamá se formó en el Mioceno medio, afectando la paleogeografía, fauna y flora marina. La Cordillera Oriental se levantó entre 12.9 y 11.8 Ma, con máxima intensidad entre 5 y 2.5 Ma, alterando ríos como el Amazonas, Orinoco y Magdalena. Un episodio frío en la Sabana de Bogotá a 2.7 Ma podría relacionarse con la glaciación del Plioceno superior. El Istmo se formó hace 3.5-3.1 Ma, desencadenando un intercambio faunístico entre América del Norte y del Sur, y durante el Pleistoceno se crearon arrecifes en el Litoral Caribe de Colombia, con edades de 300,000 a 124,000 años.
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