Dietary strategies have proven to be effective in preventing cadmium (Cd) poisoning, but the regulation of the bioavailability (BAV) and transport of Cd in the body, as well as their molecular mechanisms remain unclear. In this study, the Caco-2 cell models were applied to investigate the effects of 15 dietary supplements on Cd bioavailability (Cd-BAV) in Cd-contaminated water through a transmembrane transport assay and the mechanisms of three selected supplements in inhibiting Cd toxicity and uptake. The results demonstrated that the Cd-BAV in water varied from 7.89% to 18.4% using simulated gastrointestinal digestion and cell model. The addition of MT, Zn, and OPCs significantly reduced Cd-BAV by 82.5%, 73% and 60.5% and also strengthened transmembrane electrical resistance (TEER), indicating the protective effects of these compounds against Cd-induced barrier dysfunction. Moreover, the results of transcriptomics revealed that these components can modulate the expression of specific pathway genes associated with the toxicity and absorption of dietary Cd, such as the apoptosis pathway (Jun, Ddit3), antioxidant-related pathways (Cat, Hmox1), and mineral absorption pathway (Mt, Slc39a4). This study highlights the importance of potential dietary interventions in public health and suggests that developing more effective measures to promote safer food consumption would be beneficial.