Sediment geochemical indices and sedimentation rates data from the Pardo River watershed, São Paulo State, Brazil, provide relevant reference guidelines for stakeholders to plan future actions aiming to achieve the appropriate management of that hydrographic basin. The watershed includes 20 municipalities where about 650,000 inhabitants are living and whose waters after withdrawal and treatment supply ∼300,000 people in that region. Six sediment cores provided the geochemical and radiometric dataset, which was obtained from sampling sites located in the following cities: Ourinhos, Santa Cruz do Rio Pardo, Águas de Santa Bárbara, Avaré, Botucatu, and Pardinho. The concentration data for some metals were compared with the reference values established by the Brazilian environmental legislation for sediment dredging because currently there is a lack of specific quality guidelines for marine or fluvial sediment in Brazil. Also, the entire dataset was used in the calculation of two traditional geochemical indices, i.e., the enrichment factor (EF) and contamination factor (CF). In some cores, both indices provided insight revealing possible anthropogenic inputs of magnesium oxide (MgO), potassium oxide (K2O), sulfur trioxide (SO3), vanadium oxide (V2O5), copper (II) oxide (CuO), and other constituents due to development of activities related to the crop production. The constant rate of supply (CRS) of the unsupported/excess lead 210 (210Pb) model has been successfully applied to the obtained a radiometric 210Pb dataset, yielding mean values of the mass accumulation rate (MAR) between 0.86 and 7.23 g/(cm2·y) and linear sedimentation rates (LSR) ranging from 2.9 to 7.1 cm/y. Both of these rates exhibited a significant correlation, representing physical weathering processes occurring in the basin. Chemical weathering rates reported in the literature indicate values much lower than the physical weathering rates and such findings have also been confirmed in the current study when the obtained data were compared with results from previous investigations in the Pardo River watershed. The CRS 210Pb chronological model was useful to track historical changes in the MgO and CuO concentration in the sediment cores, allowing curves to be plotted exhibiting major peaks in core 1 (1980–2010) and core 3 (2000–2010), a continuous increase from 1970 onwards until 2010 (core 4), and a sharp increase at the end of the monitoring period, 2017 (cores 5 and 6). Data available for the harvested area at a municipality located within the basin for the period 1990–2022 have indicated a more pronounced increase over the last years in the production of sugar cane, soybeans, and oranges, implying an increasing use of fertilizers and agricultural correctives for crop production, whose chemical composition would justify the trends observed for MgO and CuO concentrations in the sediment cores. The current study also revealed a wide range of significant relations involving the concentration of ferric oxide (Fe2O3) and other analyzed constituents, with iron tending to accumulate in the finer grain sizes (from 0.125 to <0.037 mm) of the sediment. The CRS 210Pb chronological model permitted evaluation of the history of the iron flux up to the present, which could represent baseline guidance levels for indicating future anthropic inputs in the basin.