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Negative impacts of climate change on ecosystems have been increasing, and both the intensification and the mitigation of these impacts are strongly linked with human activities. Management and reduction of human-induced disturbances on ecosystems can mitigate the effects of climate change and enhance the ecosystem recovery process. Here, we investigate coupled human and climate effects on the wetland ecosystem of the lower Helmand basin from 1977 to 2014. Using time series climate-variable data and land-use changes from Landsat time series imagery, we compared changes in ecosystem status between the upstream and downstream regions. Results show that despite a strong and prolonged drought in the region, the upstream region of the lower Helmand basin remained dominated by agriculture, causing severe water stress on the Hamoun wetlands downstream. The loss of available water in wetlands was followed by large-scale land abandonment in rural areas, migration to the cities, and increasing unemployment and economic hardship. Our results suggest that unsustainable land-use policies in the upstream region, combined with synergistic effects of human activities and climate in lower Helmand basin, have exacerbated the effects of water stress on local inhabitants in the downstream region.