The quality of sediments in the mixing zone of river freshwater and marine saline water as an important geochemical barrier for potentially toxic elements (PTEs) remains poorly understood. This study aims to analyze the current pollution with PTEs and associated ecological risks in sediments of the Don River delta and the surrounding area of the Taganrog Bay of the Sea of Azov (Russia). The PTE content was determined in fifty-four collected samples using the WDXRF and assessed using geochemical and ecotoxicological indicators. The source of Cr, Mn, Ni and Pb is mainly river runoff, and Cu, Zn and Cd are from a variety of anthropogenic sources. As shown by the assessment of the geoaccumulation index (Igeo), single pollution index (PI) and contamination factor (CF), these elements are the priority pollutants. According to these estimates, high and very high contamination of sediments in the estuarine zone of the Don River with Cd and Pb was detected in 72–94% and 2–57% of samples, respectively. However, environmental risks are determined almost exclusively by the level of Cd. Total contamination as assessed by the Nemerow pollution index (NPI), modified degree of contamination (mCd) and metal pollution index (MPI) is of concern in 83–98% of the samples studied. The most heavily polluted sediments are in the vicinity of residential areas of the Taganrog Bay. Despite the lower average pollution levels of deltaic sediments, freshwater biota are exposed to higher potential toxic risks of adverse effects by PTE, particularly from Ni and Pb. Thus, the complex hydrological regime and uneven anthropogenic impact predetermine the geochemical state of the sediments of the estuarine zone of the Don River.