Knowledge of soil moisture spatial variability (SMSP) is important for many practical reasons. However, a significant gap still exists in our understanding of different controls on SMSP, especially the roles of soil hydraulic parameters due to their limited availability. Although modeling approaches have been used to assess the impacts of those parameters on SMSP, they have led to inconsistent findings. In this study, soil moisture data from Utah (5 yr) and the US Southeast (2 yr) were obtained from the Soil Climate Analysis Network (SCAN), along with estimated van Genuchten parameters. The method of mean relative difference (MRD) of soil moisture was used as a diagnostic tool for assessing different climate and soil controls on SMSP. The results show that instead of being controlled by climate variables (e.g., precipitation and potential evapotranspiration) as traditionally believed at regional scales (∼105 km2), MRD is mainly dependent on soil hydraulic properties. In Utah with a drier climate, the residual soil moisture content (θr) is the dominant control on MRD, followed by the saturated soil moisture content (θs). With wetter climates in the US Southeast, the impacts of θr and θs on MRD become comparable, mostly due to the high correlation between θr and θs in this region, and there exists a nonlinear negative relationship between MRD and the parameter n for coarser soils, indicated by larger n values tending to have lower MRDs. The findings of this study have important implications for verifying remotely sensed moisture data and initializing and parameterizing regional land surface and climate models.