The western Amazon needs to expand its protected-area system to ensure the conservation of its immense and threatened biodiversity. However, potential expansions often meet with resistance because of scarce government resources and competing social priorities. Here, we proposed an expansion of the protected-area system for the western Amazon that increases biodiversity conservation at minimum costs. We started by evaluating biological data to establish conservation targets for enhancing protection of 2419 species of plants and vertebrates. We then built a map that shows the variation in costs of effectively managing lands as protected areas. We also adapted an opportunity cost layer for agriculture and livestock to approximate realistic foregone incomes when a particular extent of land is protected. These cost estimates were used in a decision-support tool to find the most inexpensive places to achieve the conservation targets. We found that this cost-optimized expansion would reduce annual costs by 22% in comparison to an expansion planned without cost data. Moreover, without collaboration with indigenous peoples and without cooperation among the western Amazon countries costs would be 39% and 49% higher, respectively. The cost of the proposed expansion, estimated at US$ 100 million annually, is only a fraction of the regional Gross Domestic Product (0.018%). Thus, this study may help governments and conservation agencies to improve financial planning of the region's reserve network by maximizing species protection at more affordable costs.