The increasing application of metal nanoparticles (NPs) via agrochemicals and sewage sludge results in nonnegligible phytotoxicological risks. Herein, the potential phytotoxicity of ZnO and CuO NPs on wheat was determined using integrative chemical, physiological, and metabolomics analyses, in comparison to Zn2+ and Cu2+. It was found that ZnO or CuO NPs had a stronger inhibitory effect on wheat growth than Zn2+ or Cu2+. After exposure to ZnO or CuO NPs, wheat seedlings accumulated significantly higher levels of Zn or Cu than the corresponding Zn2+ or Cu2+ treatments, indicating the active uptake of NPs via wheat root. TEM analysis further confirmed the intake of NPs. Moreover, ZnO or CuO NPs exposure altered micronutrients (Fe, Mn, Cu, and Zn) accumulation in the tissues and decreased the activities of antioxidant enzymes. The metabolomics analysis identified 312, 357, 145, and 188 significantly changed metabolites (SCMs) in wheat root exposed to ZnO NPs, CuO NPs, Zn2+, and Cu2+, respectively. Most SCMs were nano-specific to ZnO (80%) and CuO NPs (58%), suggesting greater metabolic reprogramming by NPs than metal ions. Overall, nanospecific toxicity dominated the phytotoxicity of ZnO and CuO NPs, and our results provide a molecular perspective on the phytotoxicity of metal oxide NPs.