We have used Soil and Water Assessment Tool (SWAT) hydrological model to simulate the synergic effects of landuse/land cover (LU/LC) and climate change on the hydrological response of the Upper Betwa River Catchment (UBRC), a semi-arid region in Central India. We classified the Landsat satellite images of 1990 and 2018to obtain the dominant LU/LC classes (water body, built-up, forest, agriculture, and open land) in the catchment. The water body, built-up areas, and cropland have increased by 63%, 65%, and 3%, respectively, whereas forest cover and open land decreased by 16%and 23% in the UBRC from 1990 to 2018. The observed climate data in UBRC shows an increase in the average temperature and decrease in the total rainfall during the period 1980 to 2018. We set up this model for two different time periods, 1982–2000 and 2001– 2018, using the LU/LC data of 1990 and 2018, respectively. Once the model is set up, we perform the calibration and validation by using the SWAT Calibration Uncertainty Program (SWAT-CUP). We considered 1991–1994 and 2001–2007 for the calibration and 1995–1998 and 2008–2014 time period for the validation. During the calibration and validation result of our model is satisfactory. The output of our calibrated model shows a relative decrease in rainfall (12%), surface runoff (21%), and percolation (9%) in the catchment during the period 2001–2018 as compared to 1982–2000.