Soil carbon (C), nitrogen (N), and phosphorus (P) are some of the most important indicators of soil quality, especially in fragile ecological environments with shallow soils. However, the differences in their variations and influencing factors related to scale in karst areas remain unclear. Therefore, variations in surface soil organic carbon (SOC), total nitrogen (TN), and total phosphorus (TP) distributions and their determinant factors were quantitatively analyzed at different scales (i.e., region, sub-region, and catchment) in a typical karst area, southwest China. Overall, both soil nutrient variations and the determinant factors involved varied with scale. The coefficients of variation for SOC, TN, and TP increased significantly from catchment to sub-region scales but changed only slightly between sub-region and region scales. At region and sub-region scales, lithology only affected TP significantly, while land use affected all soil nutrients significantly. However, the explanations for TP variation by lithology and for SOC, TN, and TP variations by land use increased by 12.2, 7.0, 11.0, and 12.8% at sub-region scale over the values observed at region scale, respectively. When lithology and land use were controlled, soil depth was observed playing an important role in soil nutrients at the three studied scales. At region and sub-region scales, other factors related to soil texture (clay, silt, or sand content), topography (elevation or TWI), and climate (MAT or MAP) were selected as significant variables and accounted for a larger proportion of nutrient variation. However, at catchment scale, bare rock rate and micro-topography (e.g., slope) explained soil nutrient variation to a larger proportion. Therefore, elucidation of the role of factors influencing soil nutrients at different scales can provide a guide for soil quality assessment in karst areas.