Sedum plumbizincicola, a cadmium (Cd) hyperaccumulating herbaceous plant, can accumulate large amounts of Cd in the above-ground tissues without being poisoned. However, the molecular mechanisms regulating the processes are not fully understood. In this study, Transcriptional and proteomic analyses were integrated to investigate the response of S. plumbizincicola plants to cadmium stress and to identify key pathways that are potentially responsible for Cd tolerance and accumulation. A total of 6064 proteins were identified from Tandem Mass Tag (TMT) based proteome, among which 630 DAPs (differentially abundant proteins) using fold change >1.5 with p-value <0.05 were involved in processes including phenylpropanoid biosynthesis, protein processing in endoplasmic reticulum, and biosynthesis of secondary metabolites. Combined with the previous transcriptomic study, 209 corresponding genes and proteins showed the identical expression pattern. The identified genes/proteins revealed the regulatory roles of several metabolism pathways, such as phenylpropanoid biosynthesis, oxidative phosphorylation, phagosome, and glutathione metabolism, in mediating Cd tolerance and accumulation. Functional characterization of a Cd up regulated gene SpFAOMT provided insight into its role in lignin biosynthesis in S.plumbizincicola during Cd stress.