In order to investigate the factors influencing the distribution of 32 potentially toxic elements in the Ptolemais-Kozani basin, northwestern Greece, 38 soil samples were collected and analyzed. Concentrations of Al, and Zn were determined by ICP-AES and concentrations of As, Bi, Cd, Cs, Mo, Rb, Sb, Th, Tl, and U by ICP-MS. Bivariate analysis, principal component analysis, and geostatistical analysis were employed to investigate the factors influencing the distribution of the elements determined in the study area. The results indicate that the distribution of the majority of elements determined, especially for Cr, Ni, and associated elements, is greatly influenced by the geology and geomorphology of the study area. Principal component analysis has yielded four factors that explain over 77% of the total variance in the data. These factors are as follows: lithophilic elements that are associated with Al silicates minerals of K (factor I: 29.4%), ultramafic rocks (factor II: 20.5%), elements that are coprecipitated with Fe and Mn oxides (factor III: 18.0%), and anthropogenic activities (factor IV: 9.3%). The anthropogenic activities that influence the distribution of several potentially toxic elements (i.e., Cd, Cu, Pb, Zn) are agricultural practices and the deposition of fly ash in the vicinity of the local power stations.