The effect of the projected 21st century climate change on water quality in Old Woman Creek (OWC) watershed was evaluated using the Soil and Water Assessment Tool (SWAT) and the precipitation and temperature projections from three best Global Climate Circulation Model (GCM)l ensemble downloaded from the Coupled Model Intercomparison Project Phase 5 (CMIP5). These three best GCMs (GFDL-ESM2M, MPI-ESM-MR, EC-EARTH) were identified as those closest to the multivariate ensemble average of twenty different GCM-driven SWAT simulations. Seasonal analysis was undertaken in historical (1985–2014), current to near future (2018–2045), mid-century (2046–2075), and late-century (2076–2100) climate windows. The hydrological model calibration was carried out using a multi-objective evolutionary algorithm and pareto optimization. Simulations were made for stream flow and nine water quality variables (sediment, organic nitrogen, organic phosphorus, mineral phosphorus, chlorophyll a, carbonaceous biochemical oxygen demand, dissolved oxygen, total nitrogen, and total phosphorus) of interest. The average of twenty different CMIP5-driven SWAT simulation results showed good correlation for all the 10 variables with the PRISM-driven SWAT simulation results in the historical climate window (1985–2014). For the historical period, the result shows an over-estimation of flow, sediment, and organic nitrogen from January to March in simulations with CMIP5 inputs, relative to simulations with PRISM input. For the other climate windows, the simulation results show a progressive increase in stream flow with peak flow month shifting from April to March. The expected seasonal changes in each water quality variable have implications for the OWC estuary and Lake Erie water quality.