Cadmium (Cd) is a toxic heavy metal and its uptake by living organisms causes adverse effect, further resulting in cycle pollution of the biosphere. The specific regulatory mechanism between clays and microbes under Cd stress remains unclear. In this study, interface interactions among clays, microbes and Cd were confirmed. Comparative transcriptome was conducted to investigate how it regulated gene expression patterns of microbes (Chryseobacterium sp. WAL2), which exposed to a series of gradient concentrations of Cd (16, 32, 64 and 128 μg mL) for 12 d in the presence and absence of clay montmorillonite (Mt) (16 g L). Cd was highly enriched by the unique interface interactions between Mt and bacteria (67.6-82.1%), leading to a more hostile environment for bacterial cells. However, Mt ultimately enhanced bacterial resistance to Cd stress by stimulating the mechanism of bacterial resistance; namely: (i) Mt increased genes expression connected with ion transport, enhancing the uptake of Cd; (ii) Mt stimulated genes expression related to efflux pump and positively regulated cellular oxidative stress (e.g., glutathione) and Cd accumulation (e.g., cysteine) processes. Further, genes expression related to intracellular metabolic processes was enforced, which supplied a driving force and accelerated electron transfer; (iii) Mt improved genes expression involved in DNA replication and other biological processes (e.g., terpenoid backbone biosynthesis) to maintain bacterial vitality. Therefore, the study not only optimized a unique Cd resistance mechanism of Mt on Chryseobacterium sp., but also provided a novel insight for environmental mitigation of heavy metals from the perspective of molecular biology.