The hydrological responses of geographically isolated wetlands to climate change is insufficiently considered and qualified, with weak but critical hydrologic connectivity to surrounding uplands. This study simulated the essential physical hydrological processes under climate change by coupling a distributed process-based model with an assemblage of 20 general circulation models under Representative Concentration Pathway scenarios 8.5 and 4.5 for 1950–2099. A susceptibility rate was proposed to assess wetland sustainability under climate change. Different model capabilities in hydro-climatic interactions of geographically isolated wetlands were quantified by developing a process-based and an empirical model. The results show that the water table will have declined 68 cm by 2100, with decreasing water availability (−289 cm). Based on the sustainability assessment, the wetland will dry with an increasing risk from baseline of 63%–99% in 2100. The risk of wetland loss will increase from baseline of 37%–93% in 2100. The high risk of unsustainable wetlands in the study area indicates high susceptibility and vulnerability of the wetland hydrological system to climate change. The study has wide implications in conserving the entire hydrological continuum of geographically isolated wetlands and surrounded uplands. It also provides information to make adaptative strategies for wetlands under threat from climate change.