Despite growing interest in urban vulnerability to climatic change, there is no systematic understanding of why some urban centers have greater social vulnerability than others. In this article, we ask whether the social vulnerability of Amazonian cities to floods and droughts is linked to differences in their spatial accessibility. To assess the accessibility of 310 urban centers, we developed a travel network and derived measures of connectivity and geographical remoteness. We found that 914,654 people live in roadless urban centers (n = 68) located up to 2,820km from their state capital. We then tested whether accessibility measures explained interurban differences in quantitative measures of social sensitivity, adaptive capacity, and an overlooked risk area, food system sensitivity. Accessibility explained marked variation in indicators of each of these dimensions and, hence, for the first time, we show an underlying spatial basis for social vulnerability. For instance, floods pose a greater disease risk in less accessible urban centers because inadequate sanitation in these places exposes inhabitants to environmental pollution and contaminated water, exacerbated by poverty and governance failures. Exploring the root causes of these spatial inequalities, we show how remote and roadless cities in Amazonia have been historically marginalized and their citizens exposed to structural violence and economic disadvantage. Paradoxically, we found that places with the highest social vulnerability have the greatest natural and cultural assets (rainforest, indigenous peoples, and protected areas). We conclude that increasing accessibility through road building would be maladaptive, exposing marginalized people to further harm and exacerbating climatic change by driving deforestation.