Modeling scenarios can help identify drivers of and potential changes in land use, particularly in rapidly changing landscapes such as the tropics. One of the places where most of the recent anthropogenic land use changes have been occurring is the "arc of deforestation" of the Amazon, where several scenarios have been constructed. Such modeling scenarios, however, have been implemented less frequently in wetland areas, but these are also undergoing rapid change. An example is the Pantanal, one of the largest wetlands on the planet located in the Upper Paraguay River Basin (UPRB). The UPRB is formed by the lowland (Pantanal) and the plateau (Cerrado and Amazon where the spring-fed rivers are). We used a spatially explicit model to identify drivers of vegetation loss in the Pantanal and surrounding area (UPRB) and estimated potential vegetation loss for the next 30 years. The model is probabilistic and considers that vegetation loss is contagious, so that the local rate of deforestation increases over time if adjacent sites are deforested, also taking into account the drivers identified in those locations. Our study is the first to simulate vegetation loss at property-scale, over 20,000 properties, for the entire UPRB in Brazil, taking into account the relationship between the plateau, where headwaters are located, and the lowland, where flooded-areas are concentrated. The drivers of vegetation loss identified for the lowland (distance to roads and rivers and elevation) differed from those for the plateau (distance to cities), demonstrating the relevance of analyzing areas separately. The cumulative rate of native vegetation loss projected for 2050 was 3% for the lowland and 10% for the plateau, representing losses of 6045 km2 and of native vegetation area decreasing from 87% to 83% and 7960 km2 from 39% to 35% respectively by 2050, if changes continue at the same pace and if the environmental legislation is followed.The projected vegetation loss in the UPRB forms a geographical arc, very similar to that observed in the Amazon, from the plateau into the lowland. The arc is directly related to areas with no or low flooding frequency because they are suitable for agriculture. The identification of this arc of vegetation loss calls for urgent conservation policies for this wetland and new perspectives for management.