Engineered nanoparticles (NPs) with activities that mimic antioxidant enzymes have good prospects in agriculture because they can increase photosynthesis and improve stress tolerance. Here, the interaction between cerium oxide NPs with spinach plants ( Spinacia oleracea) was investigated by integrating phenotypic and metabolomic analyses. Soil-grown, four-week-old spinach plants were foliar exposed for 3 weeks to CeO2 NPs at 0, 0.3, and 3 mg per plant. Phenotypic parameters (chlorophyll fluorescence, photosynthetic pigment contents, plant biomass, lipid peroxidation, and membrane permeability) were not affected. However, metabolomics analysis revealed that both doses of CeO2 NPs induced metabolic reprogramming in leaves and roots in a non-dose-dependent manner. The low dose of CeO2 NPs (0.3 mg per plant) induced stronger metabolic reprogramming in spinach leaves than high dose of CeO2 NPs. However, the high dose of CeO2 NPs triggered more metabolic changes in roots, compared to the low dose. Foliar spray of CeO2 NPs at 3 mg/plant induced marked down-regulation of a number of amino acids (threonine, tryptophan, l-cysteine, methionine, cycloleucine, aspartic acid, asparagine, tyrosine, and glutamic acid). In addition, Zn decreased by 44% and 54% in leaves and Ca decreased by 38% and 32% in roots under exposure to CeO2 NPs at 0.3 and 3 mg/plant, respectively. These results provide better understanding of the intrinsic phenotypic and metabolic changes imposed by CeO2 NPs in spinach plants.