The dynamic nature of engineered nanoparticle (ENP) aggregation behavior and kinetics are of paramount importance in the field of toxicological and environmental nanotechnology. The Taguchi orthogonal array (OA) L27
) matrix based on a fractional factorials design was applied to systematically evaluate the contribution and significance of water chemistry parameters (pH, temperature, electrolyte, natural organic matter (NOM), content and type) and their interactions in the aggregation behavior of zinc oxide nanoparticles (ZnO NPs). The NPs were dispersed into the solution using a probe-sonicator cell crusher (Bio-safer, 1200-90, Nanjing, China). The data were obtained from UV–Vis spectroscopy (Optizen 2120 UV, Mecasys, Daejeon, Korea), Fourier Transform Infrared Spectrometery (FT-IR 4700, spectroscopy, a JASCO Analytical Instruments, Easton, Pennsylvania, USA) and particle electrophoresis (NanoZS, Zetasizer, Malvern Instruments Ltd., Worcestershire, UK). The dataset revealed that Taguchi OA matrix is an efficient approach to study the main and interactive effects of environmental parameters on the aggregation of ZnO NPs. In addition, the aggregation profile of ZnO NPs was significantly influenced by divalent cations and NOM. The result of the FT–IR data presents a possible mechanism of ZnO NP stabilization in the presence of different NOM. This data may be helpful to predict the aggregation behavior of ZnO NPs in environmental and ecotoxicological contexts.