The Basin covers more than 6,100,000 km2, or 44% of the land area of the South American continent, extending into Bolivia, Brazil, Colombia, Ecuador, Guyana, Peru, Suriname, and Venezuela.

The Amazon River basin is a massive drainage system that spans roughly 40% of the South American continent and is drained by nine different countries and territories. Brazil is the most significant, containing about 60% of the rainforest and the majority of the river's main stem. Peru follows, where the river's most distant sources originate in the Andes mountains. The other countries that make up this 7-million-square-kilometer basin include Bolivia, Colombia, Ecuador, Guyana, Suriname, and Venezuela, along with the French overseas territory of French Guiana. These nations contribute thousands of tributaries—such as the Madeira, Negro, and Marañón rivers—which eventually funnel into the Amazon, creating the largest discharge of freshwater on Earth. Because the basin crosses so many international borders, management of the river's environmental health and the protection of its indigenous territories is a complex diplomatic effort coordinated through groups like the Amazon Cooperation Treaty Organization (ACTO).