Dissolution of copper-based nanoparticles (NPs) can control their environmental persistence and toxicity. Previous research has generally reported limited dissolution of Cu-based NPs at circumneutral pH, but the environmentally important case of dissolution in solutions that are undersaturated with respect to copper mineral phases has not been investigated thoroughly. In this study, immobilized Cu-based NPs were fabricated on solid supports. Metallic copper (Cu), cupric oxide/hydroxide (Cuox), and copper sulfide (Cu x S) NPs were investigated. Dissolution rate constants were measured in situ by an atomic force microscope equipped with a flow-through cell. A mass-balance model indicated that the flowing solution was consistently undersaturated with respect to cupric solid phases. Based on the measured rate constants, Cuox NPs are expected to dissolve completely in these undersaturated conditions within a matter of hours, even at neutral to basic pH. The expected persistence of metallic Cu NPs ranges from a few hours to days, whereas Cu x S NPs showed no significant dissolution over the time scales studied. Field deployment of Cu-based NP samples in a freshwater stream confirmed these conclusions for a natural aquatic system. These results suggest that Cu and Cuox NPs will be short-lived in the environment unless dissolution is hindered by a competing process, such as sulfidation.