Grain-size distribution, major elements, nutrients and trace metals were determined in bed sediments and suspension collected at 10 representative sites along the river Po under normal and high flow conditions. Grain-size distribution and major element composition of suspension highlighted the presence of two distinct particle populations in the upper–middle Po (coarser particles, lower carbonate content) and in the lower Po (finer particles, higher carbonate content). This change partly reflects the geological differences between the two parts of the basin, and also the presence of a hydroelectric power plant at Isola Serafini (Piacenza). With respect to environmental quality issues, bed sediments and suspension provide similar results. A moderate nutrient pollution is found in all but the uppermost parts of the river basin, while the most significant inputs of trace metals appear to originate from the urban areas of Turin and Milan. Calculation of sediment enrichment factors identifies Cd, Cu, Hg and Zn as the most impacted elements by human activities. On the other hand, the high levels of Ni and Cr throughout the river seem to derive mainly from the presence of basic rocks in the upper and middle parts of the basin. Both nutrient and trace metal particulate concentrations substantially decrease under high flow conditions possibly due to “flushing” of contaminated bed sediments and resuspension of coarser material. Under normal flow conditions, water hydrochemistry and concentrations of some elements (As, Ca, Cr, Cu, K, Mg, Mn, Na, Ni, and Pb) in the dissolved phase (<0.45 μm) were also determined. Calculation of trace metals partition coefficients shows that the relative importance of the particulate and water phases varies in response to water hydrochemistry and suspended solid content, but that most elements achieve a conditional equilibrium in the lower stretches of the river Po. These results are the first of this kind reported for the whole river course and highlight the factors and mechanisms controlling the origin, mobility and fate of nutrients and trace metals in the river Po.