The rapid development of nanotechnology has raised concern regarding the environmental toxicity of nanoparticles (NPs). However, little is known about the molecular mechanisms underlying NP toxicity in plants. Broad bean (Vicia faba L.) plants were cultivated in soil amended with 0, 10, and 100 mg cadmium sulfide (CdS)-NPs per kg soil for 4 weeks, and then the phenotypic, biochemical, and metabolic responses of the plants to CdS-NP stress were evaluated. Metabolomics analysis revealed the significant up-regulation (1.2- to 39.2-fold) of several antioxidative metabolites, including N-acetyl-5-hydroxytryptamine, 2-hydroxybutanoic acid, putrescine, and flavone, upon CdS-NP exposure, but no negative phenotypic effects were visible (plant biomass, photosynthetic pigment contents, and lipid peroxidation). This observation was in accordance with the observed regulation of antioxidative-defense-related metabolic pathways (tyrosine pathway and phenylpropanoid biosynthesis) that were identified by biological pathway analysis. Importantly, twice as many metabolites were modulated in leaves than in roots, including three nitrogen-related (purine metabolism; alanine, aspartate, and glutamate metabolism; β-alanine metabolism) and two carbon-related (pantothenate and CoA biosynthesis and carbon fixation) metabolic pathways. These results indicate that to alleviate the toxicity of CdS-NP exposure in soil, plants significantly reprogram the metabolic profiles of leaves rather than of roots, which might subsequently impact both harvest and crop quality.