Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by insulin resistance (IR) and has attracted worldwide attention due to its high prevalence. As a typical persistent organic pollutant, decabromodiphenyl ether (BDE-209) has been detected in food and human samples, and the concentration trends increase year by year. In addition, it has been proved to have the potential to increase the risk of IR, but it is rarely reported whether it could aggravate IR in T2DM. Therefore, in this study, the IR-BRL (buffalo rat liver cells with IR) model was applied to study the metabolism toxicity and susceptibility of BDE-209. Results showed that BDE-209 could inhibit glucose absorption and increase the levels of serum total cholesterol (TC) and triglyceride (TG), ultimately leading to the disorder of glucolipid metabolism in IR-BRL cells. Besides, it also could cause cell damage by increasing the levels of aspartate transaminase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA) in cells. Moreover, its potential mechanisms were to: (1) affect the transport of glucose, synthesis of glycogen and fatty acid via IRS-1/GLUT4 and IRS-1/PI3K/AKT/GSK-3β pathways; (2) impact the proliferation and differentiation by regulating the expression of Mek1/2, Erk1/2, and mTOR proteins and genes. Furthermore, susceptibility analysis showed that there was a significant synergism interaction between IR and BDE-209, which suggested that IR-BRL cells were more susceptible to the metabolism toxicity induced by BDE-209.