The landscape configuration of socio-ecological land systems results from the interaction between the environmental conditions (relatively homogeneous within ecoregions) and country-level management and land-use decisions. However, social, land-use and sustainability research disciplines often study each independently. We used Euclidean distance analyses of five indicators of land systems functioning to explore the geographical patterns of across-border human-induced asymmetries in transnational ecoregions of South America. The most asymmetric transnational ecoregions occurred in the tropical rainforest biome which also showed the widest range of asymmetry values compared to other biomes. In contrast, transnational ecoregions in montane grasslands showed comparatively little asymmetries, and tropical dry forests showed intermediate asymmetry values. This pattern indicates that major asymmetries occur in land systems located in productive biomes with a comparatively recent history of development, whereas mature socio-ecosystems with a long history of human land use are more homogeneous across borders. In some cases, asymmetries may stabilize as a consequence of reinforcing feedbacks that promote contrasting land-use decisions across borders, including, for example, the establishment of protected areas, or the promotion of agro-industrial activities. Transnational socio-ecological land systems can be used to evaluate alternatives for sustainable development because they highlight the influence of institutions under different governance regimes in defining the spatial configuration and ecological properties of regions. We invite land-use and sustainability scientists to consider political border interactions as valuable “natural experiments” to better understand the interrelations between biophysical and political systems in defining planetary geographical-ecology in the Anthropocene.