Soil erosion by water is a major cause of land degradation in the highlands of Ethiopia and anywhere else in the world, but its magnitude and variability are rarely documented across land uses and climatological conditions. The purpose of this study was to examine runoff and soil loss responses under cropland (CL) and grazing land (GL) management practices in three climatic regions of the Ethiopian highlands: semi-arid (Mayleba), dry sub-humid (Gumara), and humid (Guder). We measured runoff and soil loss using runoff plots with and without soil and water conservation (SWC) measures (trenches, stone/soil bunds [embankments] with trenches on the upslope side, and exclosure) during the rainy season (July–September). The results revealed significant variation in runoff and soil loss amounts across land uses, SWC measures, and climatic regions. At Mayleba, seasonal runoff and soil loss in control plot were far higher from GL (280 mm, 26.5 t ha−1) than from CL (108 mm, 7.0 t ha−1) largely due to lack of protective vegetation cover and soil disruption because of intense grazing. In contrast, at Gumara and Guder, seasonal soil loss values were much higher from CL (21.4–71.2 t ha−1) than from GL (0.6–24.2 t ha−1) irrespective of runoff values. This was attributed to the excessive tillage/weeding operations involved in cultivation of teff (cereal crop) at Gumara and potato at Guder. Although SWC measures (practices) substantially reduced runoff and soil loss (decreased by 23%–86%) relative to control plot, seasonal soil loss under GL uses with trenches at Mayleba (12.6 t ha−1), CL with soil bunds and trenches at Gumara (22.1 t ha−1), and Guder (21.4 t ha−1) remained higher than the average tolerable soil loss rate (10 t ha−1 year−1) proposed for the Ethiopian highlands. This suggests that SWC measures should be carefully designed and evaluated specific to land use and climatic conditions. Overall, the results of this study can help improve SWC planning in regions where land use and climate impact on soil erosion vary across geographical areas, as they do in Ethiopia and anywhere else. However, further investigation is crucial with replication of measurements over years and locations to provide more accurate information on land use, management and climate controls on hydrological and soil erosion processes.