AbstractCadmium (Cd) could pose threats to human health by affectingSalvia miltiorrhiza(SM) safety. Cd enrichment trait and its effects on the active ingredient synthesis in SM remain unknown. Here we investigated the Cd concentration using ICP-MS-based method, physiologies (contents of malondialdehyde and proline, and activities of superoxide dismutase, peroxidase [POD], and catalase [CAT]), and LC-MS/MS-based metabolites of SM under 25, 50, and 100 mg kg−1Cd stress. The results revealed that Cd concentrations, as it rose in soil, increased in roots and leaves of SM with transfer factors and bioconcentration factors below 1 in Cd-treated groups; POD and CAT activities and proline content increased and then declined. Amino acids and organic acids (especiallyd-glutamine [d-Gln],l-aspartic acid [l-Asp],l-phenylalanine [l-Phe],l-tyrosine [l-Tyr], geranylgeranyl-PP [GGPP], and rosmarinic acid [RA]) contributed more in discriminating SM roots of different groups. GGPP was negatively related tol-Tyr andl-Phe, and RA was positively related tod-Gln andl-Asp in SM. These results revealed that SM belonged to a non-Cd-hyperaccumulator with most Cd accumulated in roots, Cd could enhance phenolic acid synthesis via regulating amino acid metabolism and might inhibit tanshinone synthesis by declining the GGPP content, and proline, POD, and CAT played vital roles in resisting Cd stress. These provided new ideas and theoretical basis for further study on medical plants’ response to heavy metals.