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The impact of land use/land cover and climate change on the hydrology are global issues affecting the whole catchment of the river basin. The main objective of this study was to investigate runoff response to land use/land cover change in Aynalem catchment, located in Tigray regional state, northern Ethiopia. The study analyzed the historical land cover changes from 1995 to 2015 that have taken place in the catchment and its effect on the runoff of the catchment. The land cover changes within the catchment were examined through classification of satellite images with integrated use of ERDAS Imagine (Version 9.2) and ArcGIS software. Land cover change analysis between the periods of 1995 and 2015 has shown that the urban area has increased from 1.39% to 7.50%, Cropland from 54.03% to 65.69% and Water bodies from 0.14% to 0.42%, while Planted Forest area has decreased from 3.61% to 2.92%, Grassland 2.22%-1.90% and Open Shrub lands from 38.61% to 21.53%. Further, Water and Energy Transfer between Soil, Plants, and Atmosphere (WetSpa) model was used to investigate the runoff response to a land cover change on the study area. The model was calibrated (1994-1998) and validated (1999-2001) against the observed daily stream flow data. WetSpa model parameters sensitivity analysis result shown that the groundwater recession coefficient (Kg), Initial active groundwater storage (Go) and Surface runoff exponent (K_run) are the most sensitive parameters affecting the hydrology of the catchment. The WetSpa model application in Aynalem catchment performances very good in reproducing the hydrological process of the catchment with coefficient of determination (R-2), Nash and Sutcfiff efficiency (NSE) values of 0.82 and 0.90 for calibration, 0.78 and 0.88 for validation, respectively. The WetSpa model application with land useland cover maps of 1995, 2003 and 2015 shows annual runoff increased by 21.1% from the year of 1995-2003 and 23.5% from 2003 to 2015 and also, 44.6% from 1995 to 2015. The increment in runoff is likely to have been caused by the change of the land use/land cover from shrubs and grass lands to urban and cultivated lands.