In the Syr Darya River watershed, 225 samples from three different layers in 75 soil profiles were collected from irrigated areas in three different spatial regions (I: n = 29; II: n = 17; III: n = 29), and the spatial and vertical variation characteristics of potentially toxic elements (Cd, Co, Cu, Ni, and Zn) and a metallic element (Mn) were studied. The human health risks and enrichment factors were also evaluated in the Syr Darya River watershed of the Aral Sea Basin in Kazakhstan. There were significant differences in the contents of heavy metals in the different soil layers in the different sampling regions. Based on element variation similarity revealed by hierarchical cluster analysis, the elemental groupings were consistent in the different layers only in region I. For regions II and III, the clustered elemental groups were the same between surface layer A and B, but differed from those in the deep layer C. In sampling region I, the heavy metals in surface soils were significantly correlated with the ones in deep layers, reflecting that they were mainly affected by the elemental composition of parent materials. In region II, the significant correlations only existed for Cu, Mn, and Zn between the surface and deep layers. The similar phenomenon with significant correlation was also observed for heavy metals in sampling region III, except for Cd. Finally, enrichment factor was used to study the mobilization and enrichment of potentially toxic elements. The enrichment factors of Zn, Cu, and Cd in surface layer A that were greater than 1.5 accounted for 1.16%, 6.79%, and 24.36% of sampling region I, respectively. In sampling region II, the enrichment factors of Zn, Cu, Cd, and Co that were greater than 1.5 accounted for 0.03%, 4.76%, 0.54%, and 9.03% of the total area, respectively. In sampling region III, only the enrichment factors of Zn, Cu, and Cd that exceeded 1.5 accounted for 0.24%, 4.90%, and 6.89% of the total area, respectively. Although the contents of the heavy metals were not harmful to human health, the effects of human activities on the heavy metals in the irrigated soils revealed by enrichment factors have been shown in this study area.