<p>Deforestation in Brazilian Amazon impacts ecosystem services, affects the Amazonian population, and contributes to global warming. Public policies promoting highway construction pose a major threat to a critical area of undesignated public forests in Brazilian Amazonia: the Trans-Purus region—a vast forest area west of the Purus River in Amazonas state. The forest in this region is largely intact, as its inaccessibility by road makes it less attractive to land grabbers, but it could become a new deforestation hotspot if planned highways are built. We projected the potential impact of planned highways on deforestation and the advance of illegal land occupation under a business-as-usual scenario in the Trans-Purus region and its surrounding areas, including the BR-319 highway region to the east, the Humaitá and Lábrea areas to the south, the Juruá area to the west, and the Manaus influence region to the north. A baseline scenario (without highways) was also simulated for comparison. The business-as-usual scenario showed a reduction of 15% of remaining forest from 2022 to 2070. The increase in deforestation between the business-as-usual and baseline scenarios was greater in the Trans-Purus region than in any of the four surrounding regions we simulated. In the Trans-Purus region, the mean annual deforestation increased from 23 to 483 km² with the highways, and undesignated public forests showed substantial deforestation, demonstrating the role of highways in facilitating the access of actors from Brazil’s “arc of deforestation.” The magnitude of potential impacts implies the need to reconsider government policies on Amazon development that rely on highway projects.</p>