Large tropical rivers provide essential societal benefits, including food production, irrigation, hydropower, transportation, and trade routes. However, these human activities pose unprecedented challenges to the integrity of the river systems, a problem that, in most cases, occurs without fully understanding the natural dynamics of these valuable ecosystems. Here, we synthesize the status of recent and long-term (decades-centuries) anthropogenic impacts occurring in one of the world's hotspots of tropical fish diversity, the Magdalena River, Colombia. Unfortunately, the Magdalena River has attracted little research attention compared to similar tropical rivers. We seek to promote research on the compounding impacts of climate change, river impoundment, alien invasive species, catchment deforestation, and water pollution on the Magdalena and the ecosystem services it provides.