Subsurface drainage modifications are a common practice in agricultural watersheds, especially in poorly drained soils of the American Midwest, yet our understanding of their impact on baseflow generation processes is incomplete. By extension, these same practices can make baseflow vulnerable to salinization. To address these knowledge gaps, a combined geochemical and multiple isotope approach was used to identify sources of baseflow and salinity in the Wabash River, draining Indiana, Ohio, and Illinois. Anomalously high salinity and high concentrations of F−, SO42−, Na+, Sr2+, and K+ were measured in baseflow along the headwaters reach of the Wabash River from Fort Recovery, OH to Huntington, IN. Three river sites in the headwaters reach have low 36Cl/Cl ranging from 27.5 (x 10−15) to 33.4 (x 10−15) that do not fall within the 36Cl/Cl range for monthly precipitation. Their 36Cl/Cl are consistent with 36Cl dilution most likely due to the presence of old Cl− found in potash (KCl) fertilizers. However, the 87Sr/86Sr ratios of the headwaters reach range from 0.708530 to 0.708904 (+/- 0.000025) and are similar to Silurian bedrock samples (0.708292 +/- 0.000047) indicating a geologic source for some solutes. The δ18O of the headwaters reach are isotopically light and similar to cold-season recharge, whereas the δ18O of the downstream river samples are similar to summer precipitation. The Cl−, NO3–, Cl−/Br−, and 36Cl/Cl data point to an anthropogenic source of salinity, namely KCl and road salt, whereas the F−, Sr2+, SO42−, and 87Sr/86Sr data point to a geologic source of solutes. We infer that shallow groundwater that is Cl− and NO3– rich mixes in the river with regional groundwater that is Cl− and NO3– poor. The contribution of regional groundwater to baseflow in the headwaters reach is not insignificant (>58 percent) and these interactions should be considered in future hydrologic models of the Upper Wabash River. Without the aid of multiple isotopic and geochemical tracers, baseflow generation processes and sources of salinity in the headwaters reach would remain masked by the elevated solute concentrations associated with the shallow aquifers. Further research is needed to better understand the impact of KCl fertilizers on the overall salinity budgets of agricultural watersheds.