Possible consequences of climate change in one of the world's largest wetlands (Ibera, Argentina) were analysed using a multi-scale approach. Climate projections coupled to hydrological models were used to analyse variability in wetland water level throughout the current century. Two potential scenarios of greenhouse gas emissions were explored, both resulting in an increase in the inter-annual fluctuations of the water level. In the scenario with higher emissions, projections also showed a long-term negative trend in water-level. To explore the possible response of biota to such water-level changes, species-area relationships of flora and aerial censuses of macro-fauna were analysed during an extraordinary dry period. Plant species richness at the basin scale was found to be highly resistant to hydrological changes, as the large dimension of the wetland acts to buffer against the water-level variations. However, local diversity decreased significantly with low water levels, leading to the loss of ecosystem resilience to additional stressors. The analysis of macro-fauna populations suggested that wetland provides refuge, in low water periods, for the animals with high dispersal ability (aquatic and migratory birds). On the contrary, the abundance of animals with low dispersal ability (mainly herbivorous species) was negatively impacted in low water periods, probably because they are required to search for alternative resources beyond the wetland borders. This period of resource scarcity was also related to increased mortality of large mammals (e.g. marsh deer) around water bodies with high anthropogenic enrichment and cyanobacteria dominance. The synergy between recurrent climatic fluctuations and additional stressors (i.e. biological invasions, eutrophication) presents an important challenge to the conservation of neotropical wetlands in the coming decades.