Soil erosion by water is one of the most pressing environmental challenges in Ethiopia where small-scale agriculture is the main source of livelihood for about 87% of country’s population. In the past few decades, huge financial and labor resources have been invested for the implementation of sustainable land management (SLM) practices in many regions of Ethiopia to mitigate soil erosion and related consequences. Relevant studies are, however, limited for the wetter and actively eroding regions like the Upper Blue Nile basin due partly to insufficient policy attention and difficulties inherent in collecting sufficient and reliable runoff, soil, and sediment data at wider spatial and temporal scales. This study was, therefore, conducted in three contrasting agro-ecologies (lowland, midland, and highland) of the Upper Blue Nile basin to quantify the influence of land use and management practices on runoff, soil loss (SL), and soil properties. The analysis of runoff and SL was based on the data collected during the rainy seasons of 2015 and 2016 using runoff plots (30 m × 6 m) from three land use types (cropland, grazing land, and degraded bushland) with four treatments (control, soil bund, Fanya juu, and soil bund reinforced with grass) for croplands, and three treatments (control, and exclosure with and without trenches) for non-croplands (grazing land, and degraded bushland). Topsoil (0–20 cm) samples were collected from the runoff plots in 2015 (at the beginning of the experiment) and 2018 (three years later) and analyzed for nine soil properties—texture, bulk density (BD), pH, electrical conductivity (EC), cation exchange capacity (CEC), total nitrogen (TN), soil organic carbon (SOC), available phosphorus (Pav), and available potassium (Kav). The results show that runoff, SL, and soil properties varied greatly across land use and SLM practices in all three agro-ecologies. The highest rates of both seasonal runoff (898 mm in 2016) and SL (39.67 t ha−1 in 2015) were observed from untreated grazing land in the midland agro-ecology, largely because of heavy grazing and intense rain events. Whereas, the lowest values of pH, CEC, SOC, and TN values were observed in croplands, probably owing to unsustainable cropping systems practiced over centuries. In all agro-ecologies and land use types, both runoff and SL were significantly lower (P < 0.05) in plots with SLM than without: SLM practices reduced runoff by 11% to 68%, and SL by 38% to 94% depending of land use and agro-ecology, and sensitive soil properties (BD, SOC, TN, Pav, and Kav) were markedly improved three years after the implementation of SLM practices. Soil bund reinforced with grass in croplands and exclosure with trenches in non-croplands were found to be the most effective SLM practices for reducing runoff and SL, and improving soil properties, indicating that combined structural and vegetative measures are the best way to control soil erosion and related consequences.