Many river basins are facing a reduction of flows which might be attributed to changes in climate and human activities. This issue is very important in transboundary river basins, where already existing conflicts about shared water resources between riparian countries can easily escalate. The decrease of streamflow in the transboundary Hirmand (Helmand) River is one of the main challenges for water resources management in Iran and Afghanistan. This research aims to quantify the causes of this problem which has a direct impact on the dryness of the Hamoun wetlands being an international Ramsar site. To achieve this, the land use changes in the Middle Helmand Basin (MHB) in Afghanistan were evaluated for three time periods between 1990 and 2011 using remote sensing data and the Soil and Water Assessment Tool (SWAT) Model for understanding watershed response to environmental changes. It was concluded that the total irrigated area in the region has increased from 103,000 ha in 1990 to 122,000 ha in 2001 and 167,000 ha in 2011 (62% increase). According to the results, the average annual discharge when adapting the land use during the simulations was 4,787 million cubic meters (MCM)/year and while employing the land use of 1990 from the beginning of the simulations, the average annual discharge was 5,133 MCM/year. Therefore, the agricultural developments in the Helmand basin decreased the discharge with about 346 MCM/year accompanying an increase of 64,000 ha in an irrigated area in MHB after 1990. Notably, the impact of land use change increases significantly for more recent periods and causes a reduction of 810 MCM in annual streamflow for the MHB. The amount of water depletion (i.e. actual evapotranspiration) per hectare has increased from 5,690 in 1985 to 7,320 m3 in 2012. The applied methodology of this study is useful to cope with such a data scarcity region. It can help quantify the impact of land use change on the region and formulates strategies that can improve the situation between Iran and Afghanistan.