The expansion of cultivated land in place of natural vegetation has a substantial influence on hydrologic characteristics of a watershed. However, due to basin characteristics and the nature and intensity of landscape modification, the response varies across basins. This study aims to evaluate the performance of a soil and water assessment tool (SWAT) model and its applicability in assessing the effects of land use land cover (LULC) changes on the hydrological processes of the upper Genale River basin. The results of satellite change detection over the past 30 years (between 1986 and 2016) revealed that the landscape of the basin has changed considerably. They showed that settlement, cultivated, and bare land areas had increased from 0.16% to 0.28%, 24.4% to 47.1%, and 0.16% to 0.62%, respectively. On the contrary, land cover units such as forest, shrubland, and grassland reduced from 29.6% to 13.5%, 23.9% to 19.5%, and 21.8% to 18.9%, respectively. Based on monthly measured flow data, the model was calibrated and validated in SWAT-CUP using the sequential uncertainty fitting (SUFI-2) algorithm. The result showed that the model performed well with coefficient of determination (R2) ≥ 0.74, Nash–Sutcliffe efficiency (NSE) ≥ 0.72, and percent bias (PBIAS) between −5% and 5% for the calibration and validation periods. The hydrological responses of LULC change for the 1986, 2001, and 2016 models showed that the average annual runoff increased by 13.7% and 7.9% and groundwater flow decreased by 2.85% and 2.1% between 1986 and 2001 and 2001 and 2016, respectively. Similarly, the total water yields increased from 324.42 mm to 339.63 mm and from 339.63 mm to 347.32 mm between 1986 and 2001 and 2001 and 2016, respectively. The change in hydrological processes, mainly the rise in runoff and total water yield as well as the reduction in lateral and groundwater flow in the watershed, resulted from LULC changes. This change has broader implications for the planning and management of the land use and water resource development.