Bisphenol S (BPS), a widely used substitute for bisphenol A (BPA), has been implicated in metabolic disorders and obesity, yet its effects on adipose tissue thermogenesis remain unclear. This study combined network toxicology prediction with experimental validation to investigate the underlying mechanisms of BPS in adipose tissue thermogenesis. In vitro, BPS significantly suppressed beige adipocyte differentiation in C3H/10T1/2 cells, reducing expression of thermogenic markers uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In vivo, BPS exposure in C57BL/6J mice led to impaired thermogenesis, adipocyte hypertrophy, and reduced cold tolerance. Molecular docking analysis revealed a strong binding affinity between BPS and Cytochrome P450 Family 2 Subfamily E Member (CYP2E1), with a binding free energy of -7.5 kcal/mol. Subsequent in vitro functional assays confirmed that BPS stabilized CYP2E1 protein levels and prolonged its half-life. Crucially, genetic knockout of CYP2E1 significantly attenuated BPS-induced suppression of Adipocyte beiging, identifying CYP2E1 as the key mediator. These findings demonstrate BPS inhibits white adipose tissue beiging by targeting CYP2E1 and disrupting its protein degradation, thereby suppressing energy expenditure. Collectively, the study provides mechanistic insights into BPS-induced metabolic dysfunction and highlights the need to reevaluate the safety of BPS as a BPA alternative, suggesting CYP2E1 as a potential therapeutic target for counteracting environmental obesogen effects.