The aim of the current research was to assess the association between the exposure to plastic-related chemicals and toxic metals with the development of type 2 diabetes mellitus using an in silico approach, while also exploring the protective potential of antioxidant vitamins and phytochemicals, including Vitamin C, Vitamin E, sulforaphane, resveratrol, curcumin, naringin, and quercetin. CTD database, GeneMANIA server, and Toppgene portal were used as the main in silico tools in this study. Six common genes (BAX, CASP3, CAT, IL6, SOD1, TNF) were identified for all toxic substances, indicating potential shared mechanisms of toxicity (apoptosis, inflammation, oxidative stress). Additionally, phthalates and bisphenols affected cell growth, lipid and energy metabolism, and vascular functions, while toxic metals were linked to apoptosis regulation, DNA repair, insulin regulation, and glucose uptake. All tested protective substances, except naringin, affected all six common genes for all toxic substances, with vitamin C, vitamin E, and sulforaphane showing the most consistent protective effects. This study highlights the complex mechanisms in type 2 diabetes pathogenesis induced by toxic substances and provides a foundation for further research on the preventive effects of tested protective substances, emphasizing their varying protective potentials depending on the toxic compounds.