Psammosilene tunicoides is an herbal medicine with analgesic, anti-inflammatory and immunoregulatory properties, and it is listed as an International Union for the Conservation of Nature (IUCN) endangered species. The plants have been domesticated in some areas of Yunnan Province, China, for commercial and medical use. However, the performance of domesticated plants and the negative effects of domestication remain unclear. Multi-omics analyses were performed to compare the performance between wild P. tunicoides (WP) and cultivated P. tunicoides (CP). Transcriptomic and metabolomic data were generated from the roots, while microbiome data were obtained from the rhizospheres. The transcriptomic data showed that there were different patterns of gene expression between the WP and CP. The genes HMGS, HMGR, MPD and SQS, which are involved in the biosynthesis of triterpenoid saponins, were significantly more highly expressed in the WP than in the CP. The metabolomic analysis also found that significantly more triterpenoids were produced in the WP compared with the CP. The microbiome data showed that most of the plant growth-promoting rhizobacteria (PGPR), such as Burkholderia-Caballeronia-Paraburkholderia and others, were enriched in the WP type, while some pathogenic microorganisms were enriched in the CP type. A weighted gene co-expression network analysis revealed that the accumulation of triterpenoid saponins positively correlated with the modules of genes that primarily participated in the plant hormone signal transduction pathway and the PGPR in modules. This indicated that the triterpenoid saponins may function as signaling molecules to recruit the functional microbes. The regulatory “plant-microbe” network of microorganisms and the genes associated with triterpenes was detected in P. tunicoides. This suggests that the management of these interactions should be considered as a sustainable tool to enhance the performance of domesticated plants.