Soil characterization is crucial in creating sustainable platforms for land users to identify areas vulnerable to anthropogenic activities. This study was conducted to investigate the impacts of lithology, slope, and land use on soil properties of a semi-arid highland in northern Ethiopia. Disturbed and undisturbed soil samples collected from 0 to 30 cm depth were analyzed. Most of the assessed physical and biochemical soil properties varied significantly (p < 0.05) with lithology, slope class, and land use type. Shale-originated soils were richer in nutrients than soils of other lithologies. A decrease in slope gradient accounted for an increase in most soil properties, while a reverse trend was observed for sand content, bulk density (BD), water stable aggregates (WSA), mean weight diameter (MWD), structural stability index (SSI), soil organic carbon (SOC), total nitrogen (TN), and available phosphorus (AP). Silt and clay fractions, total porosity, moisture content at field capacity and wilting point, visual evaluation of soil structure, pH, electrical conductivity, calcium carbonate, exchangeable bases, cation exchange capacity, and percent base saturation were found to be higher for cultivated land soils compared to grass land and shrub land soils. Shrub land soils, in contrast, had higher WSA, MWD, SSI, SOC, TN, and AP relative to grass land and cultivated land soils. In summary, slope class and land use type stood out as the major drivers influencing the dynamics and distribution of soil properties other than lithology and their interactions in semi-arid highlands of northern Ethiopia. Thus, from sustainability point of view and in the light of their nutrient retention capability and limitation, more attention should be paid toward ensuring periodic assessment and sustainable management of soils in steep cultivated lands.