In the Amazon, aquatic ecosystems provide essential ecosystem services, including transportation, food, and livelihoods for millions of species. Land use changes and management impact these ecosystem services and these impacts are not limited to the specific areas where they occur but propagate downstream along the drainage network. However, assessment of the accumulated human footprint upstream of Amazonian rivers has been largely overlooked. Here, we provide explicit spatial information on accumulated deforestation, mining, and protection across the river network. We aim to indicate the most impacted rivers and where the consideration of the watershed concept could improve the security of Conservation Units and Indigenous Lands in the Amazon. Our results show that 50% of the Amazonian rivers are pristine (less than 1% deforestation upstream), and 5% have some upstream mining area. However, almost half of the rivers in protected areas are, in truth, unprotected because the delimitation of the protected area does not cover its upstream drainage areas. Finally, our analyses identify hotspots of accumulated deforestation and mining and highlight the potential vulnerability of the rivers within protected areas due to upstream deforestation, allowing decision-makers to rethink the conservation status of the Amazonian aquatic ecosystems.