Phytochelatins (PCs) play a vital role in the tolerance and enrichment of cadmium (Cd) in higher plants by chelating with Cd2+. The aim of this study was to perform a full-scale metabolomics analysis of metabolic responses highly correlated with PCs generation. These metabolites and metabolic pathways were expected to promote PCs generation and further optimize Cd absorption in plants. In the current study, Amaranthus hypochondriacus, a potential species for phytoremediation, was first adopted to investigate physiological responses to Cd stress via LCMS/MS-based metabolomics and the HPLC based determination of thiol compounds. The results showed that the leaves of A. hypochondriacus under high Cd stress accumulated 40 times the amount of Cd compared to the leaves of the plants not under Cd stress and had an increased content of three types of PCs. Metabolomics qualitatively identified 12084 substances in total, among which 41 were significantly different metabolites (SDMs) between the two groups and involved in 7 metabolic pathways. Among the SDMs, 12 metabolites were highly linearly correlated with PCs involved in three pathways (Val, Leu and Ile biosynthesis; Ala, Asp and Glu metabolism; and Arg and Pro metabolism). These results provide an innovative method to promote PCs synthesis for the restoration of Cd-contaminated-soil.