To better understand the environmental behavior, fate, and exposure risks of engineered nanoparticles in aquatic systems, for the first time, combinatorial aqueous systems were established using three-level orthogonal array design (OAD), an OA27 (3(1)(3)) matrix, to assess the effects of six co-varying environmental factors (organic acid type, organic acid concentration, NP concentration, pH, salt content, and electrolyte type) on the aggregation of commercial zinc oxide nanoparticles (ZnO NPs, mean diameter ∼41nm). A separate set of OA27 (3(1)(3)) experiments including temperature was conducted for the dissolution of these NPs. The results showed that the organic acid concentration and the pH were the most significant factors (p<0.001) influencing aggregation and dissolution of ZnO NPs, respectively. The electrolyte type and the salt content were the next most important factors in both the aggregation and dissolution. Based on the kinetics study of the aggregation, a high rate of the NP aggregation resulted in decreased dissolution, such that observed in the presence of calcium chloride. Clear temperature-induced aggregation and reduced dissolution were further observed with increasing temperature. This approach demonstrates that the behavior of ZnO NP may vary substantially under combinatorial environmental conditions.