Hydrological responses vary from one catchment to another, depending on the nature of land use and cover changes. Modelling the hydrological responses to changes in land use and cover at different catchment spatial scales was the major focus of this study. This study assessed the hydrological responses attributed to changes in land use and extreme weather events resulting into increased sediment loading/concentration, rainfall-runoff generation/volume, streamflow fluctuation and modification of the river channel in the Malaba River Catchment, Eastern Uganda. The hydrological responses were assessed using hydrological models (IHACRES, SCS CN, and SHETRAN) to examine the effect of land use on soil physio-chemical properties susceptibility to rainfall-runoff generation and volume, frequency and severity of extreme weather events, changes in streamflow variations, sediment loading/concentration and river channel morphology. The preliminary study results showed that the frequency of extreme weather events reduced from 4-10 to 1-3 years over the catchment. The performance of the IHACRES model with a Nash-Sutcliffe Efficiency (NSE) of 0.89 showed that streamflow comparatively corresponded with the results obtained the drought indices in predicting the recorded events of severe drought (2005) and flood (1997). Changes in land use and cover types showed that the highest change in the gain of land was experienced from the agricultural land use (36.7 percent), and tropical forest (regeneration) (2.2 percent). The biggest losses in land were experienced in the wetlands (24.6 percent) and bushland and thickets (15.3 percent) land cover types. The SHETRAN model calibrated period had a NSE of 0.78 and 0.81 in the validation period showed satisfactory fits between the measured and simulated streamflow. The agricultural land use (crop growing) had a higher influence on the rainfall-runoff generation and increase in the streamflow than the tropical forest, and bushland cover types in the simulated period. Similarly, the curve number model estimated a comparatively higher surface rainfall-runoff volume generated from the agricultural land use (crop growing) (71,740 m3) than in the bushlands and thickets (42,872 m3) from a rainstorm followed by the tropical forest cover type. This was also reflected in the lower rates of saturated hydraulic conductivity from the agricultural land use (crop growing). The study also showed that human-induced sediment loading due to gold mining activities contributed a much higher impact on the concentration of suspended sediments and streamflow than sediments from rainfall-runoff from the sampled streams. The main contributor of human-induced sediments to the Malaba River were Nankuke River (130.6kg/annum), followed by Omanyi River (70.6kg/annum), and Nabewo River (66.8kg/annum). Human-induced sediment loading had a profound impact on the streamflow variations both in the dry and wet seasons from the sampled tributaries. Lastly, in regard to the effect of land use and cover types on the river channel morphology, tree plantation (cohesion=12, angle of internal friction=27) and bushland and thickets (cohesion=14, angle of internal friction=22) cover types had the most stable river banks compared to the wetland and agricultural land use and cover types that exhibited higher levels of sediment concentration.