The Nhecolândia region covers the southern wetlands of the Pantanal basin in Brazil. Characterized by myriad shallow freshwater and alkaline–saline lakes, the distinct natural features of the Nhecolândia wetland make it highly sensitive to climate change and the effects of human activities. This paper summarizes the natural and social aspects that have affected this delicate wetland and potential future impacts. We analysed the response of the wetland to historical changes in climate and human activity and used this understanding to forecast the response of the wetland to future changes. The data presented here show that this region is particularly sensitive to alterations in the flood regime, droughts and deforestation, which are intrinsically related to both global and local changes in climate and the intensification of cattle-ranching activities, which include deforestation and the introduction of cultivated pastures.