Polar compounds from frying oils have been found to be harmful to health. However, the mechanisms underlying this phenomenon have largely remained elusive. In this study, mass spectrometry-based metabolomics was used to investigate the toxicological effects of polar compounds. The serum and hepatic metabolites from polar compound-treated mice were measured using liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. Multi-variate statistical analysis showed that a total of 36 serum metabolites and 18 hepatic metabolites were altered in the polar compound-treated mice as compared with that for normal diet-fed animals. These metabolic changes suggested novel alterations in lipid metabolism with the increase in phospholipids, fatty acids, and cholesterol and the decrease in choline, betaine and l-acetylcarnitine. The TCA cycle and carbohydrate, amino acid and purine metabolism were also impaired, with a significant elevation of d-glucose, d-maltose, β-mannobiose, branched chain amino acids, aromatic amino acids, and uric acid and a decline in succinate, serine, aspartate, arginine and ornithine. Pearson correlation analysis demonstrated the strong correlations between specific metabolic alterations and the redox index. Our overall findings reveal that polar compounds may progressively cause lipid deposition, impaired energy metabolism and oxidative stress, resulting in toxicological effects on the mammalian health.