Water quality and quantity can be influenced by transit through and storage in reservoirs. Assessing such effects can be challenging, however, because of mixing and residence times, and inter-annual net storage and release from both the reservoir itself and surrounding porosity. Here, different methodologies were used to assess the effect of John Martin Reservoir (JMR), located on the Arkansas River, on water volumes and the problematic constituents salinity (total dissolved solids, TDS), selenium (Se), and uranium (U). Methodologies addressed short-term (16 months) and long-term (31 years) effects depending upon data availability. Evaporation was assessed by using isotopes of water to determine 12% short-term evaporation, and by pan evaporation and changes in storage to determine 11% long-term evaporation. Salinity, Se, and U mass balance were assessed by using chloride (Cl−) as an index by which to measure short-term gains or losses between inflows and outflows in the short term. Chloride gain from ungaged inflows skewed those results to overestimate retention. Continuous monitoring of discharge and specific conductance for inflows and outflows, along with discrete sampling for dissolved constituents were used to compute long-term, load-based mass balance. Mild gains of TDS (34,000 ± 15,000 Mg/yr) and U (0.1 ± 0.5 Mg/yr) in JMR were detected. Although the additions are small relative to uncertainty, they indicate little to no retention of TDS and U and likely additions from ungaged inflows. In contrast, an average of 0.6 ± 0.2 Mg/yr or 23% of gaged inflow Se was removed in JMR. The study illustrates the benefit of long-term records for assessing the influence of reservoirs for which net storage and release keep them from approaching steady-state conditions.