The interaction of climate change and increasing anthropogenic water withdrawals is anticipated to alter surface water availability and the transport of carbon (C), nitrogen (N), and phosphorus (P) in river networks. But how changes to river flow will alter the balance, or stoichiometry, of these fluxes is unknown. The Lower Flint River Basin (LFRB) is part of an interstate watershed relied upon by several million people for diverse ecosystem services, including seasonal crop irrigation, municipal drinking water access, and public recreation. Recently, increased water demand compounded with intensified droughts have caused historically perennial streams in the LFRB to cease flowing, increasing ecosystem vulnerability. Our objectives were to quantify how riverine dissolved C:N:P varies spatially and seasonally and determine how monthly stoichiometric fluxes varied with overall water availability in a major tributary of LFRB. We used a long-term record (21-29 years) of solute water chemistry (dissolved organic carbon, nitrate/nitrite, ammonia, and soluble reactive phosphorus) paired with longterm stream discharge data across six sites within a single LFRB watershed.We found spatial and seasonal differences in soluble nutrient concentrations and stoichiometry attributable to groundwater connections, the presence of a major floodplain wetland, and flow conditions. Further, we showed that water availability, as indicated by the Palmer Drought Severity Index (PDSI), strongly predicted stoichiometry with generally lower C:N and C:P and higher N:P fluxes during periods of low water availability (PDSI < −4). These patterns suggest there may be long-term and significant changes to stream ecosystem function as water availability is being dramatically altered by human demand with consequential impacts on solute transport, in-stream processing, and stoichiometric ratios.