Bisphenols A (BPA) and S (BPS) are endocrine-disrupting chemicals that affect energy metabolism, leading to impairment of glucose and lipid homeostasis. We aimed at identifying metabolic pathways regulated by both compounds in human liver cells and rat pancreatic β-cells that could impair energy homeostasis regulation. We assessed the effects on growth, proliferation, and viability of hepatocarcinoma (HepG2) and insulinoma (INS-1E) cells exposed to either BPA or BPS in a full range concentration between 0.001 and 100 μM. Both the dose and duration of exposure caused a differential response on growth and viability of both cells. Effects were more pronounced on HepG2, as these cells exhibited non-linear dose-responses following exposure to xenobiotics. For INS-1E, effect was observed only at the highest concentration. In addition, we profiled their intracellular state by untargeted metabolomics at 24, 48, and 72 h of exposure. This analysis revealed time- and dose-dependently molecular changes for HepG2 and INS-1E that were similar between BPA and BPS. Both increased levels of inflammatory mediators, such as metabolites pertaining to linolenic and linoleic acid metabolic pathway. In summary, this study shows that BPS also disrupts molecular functions in cells that regulate energy homeostasis, displaying similar but less pronounced responses than BPA. Display omitted •BPA and BPS reduced AAs and nucleosides and increased PUFAs metabolites in HepG2.•BPA altered INS1-E metabolic profile, increasing ceramides and PUFAs levels.•BPA and BPS display similar toxic effects; however, BPA has higher toxic potential.•Both BPA and BPS play key roles in regulating inflammation in HepG2 and INS-1E.