Nutrients, total dissolved solids (TDS), and trace elements affect the suitability of water for human and natural needs. Here, trends in such water-quality constituents are analyzed for 1999–2022 for eight nested monitoring sites in the 24,000 km2 Fountain Creek watershed in Colorado, USA, by using the weighted regressions on time, discharge, and season (WRTDS) methodology. Fountain Creek shares characteristics with other western U.S. watersheds: (1) an expanding but more water-efficient population, (2) a heavy reliance on imported water, (3) a semiarid climate trending towards warmer and drier conditions, and (4) shifts of water from agricultural to municipal uses. The WRTDS analysis found both upward and downward trends in the concentrations of nutrients that reflected possible shifts in effluent management, instream uptake, and water conservation by a watershed population that grew by about 40%. Selenium, other trace elements, and TDS can pose water-quality challenges downstream and their concentrations were found to have a downwards trend. Those trends could be driven by either a warming and drying of the local climate or decreased agricultural irrigation, as both would reduce recharge and subsequent mobilization from natural geologic sources via groundwater discharge. The patterns illustrate how changes in climate and water use may have affected water quality in Fountain Creek and demonstrate the patterns to look for in other western watersheds.