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Colombia is one of the most biodiverse countries in the world that has historically and is currently experiencing extensive deforestation and habitat fragmentation. Here we show how the most extensive region acting as a natural corridor between the Colombian Andes and Amazon biogeographical regions, the Picachos-Tinigua-Sierra de la Macarena-Chiribiquete megacorridor, is being eroded by large-scale agricultural expansion endangering the maintenance and connection of gene flow and biodiversity exchange. Several phylogenetic studies indicate that the complex dynamics between the Andean highlands and the Amazonian lowlands have strongly influenced the origin and maintenance of Neotropical biodiversity. We appeal for the attention of international conservation and governmental organizations to direct resources and promote projects focused on the preservation and sustainable management of this strategic Andes-Amazon bridge in both protected and unprotected areas. In the current postconflict era, Colombia has a unique opportunity to create a new social and economic paradigm based on long-term sustainably developed landscapes and more equitable sharing of wealth. We believe improved management and conservation efforts for the Picachos-Tinigua-Macarena-Chiribiquete megacorridor would demonstrate a collective will in helping to achieve this goal.