In this study, a metabolomics approach was applied to investigate the metabolic responses of grey mullet, Mugil cephalus to toxicity induced by heavy metal, Pb (NO3). In addition, the study was followed by assessing the peroxidation index and histology of liver as supplementary data. Pb (NO3) exposure affected the plasma metabolome, especially four group metabolites including amino acids, methylated metabolites, energetic metabolites and citric acid intermediates. Pb (NO3) in medium and high concentrations (15 and 25 μg/l) increased the levels of plasma amino acids compared to control (P < 0.01). In contrast, Pb (NO3) decreased the plasma levels of methylated metabolites (P < 0.01). The ketogenic metabolites and glycerol levels significantly elevated in fish exposed to 25 μg/l Pb (NO3) (P < 0.01). The plasma glucose levels increased in treatment, 5 μg/l Pb (NO3) and after a decline in treatment 15 μg/l Pb (NO3) elevated again in treatment 25 μg/l Pb (NO3) (P < 0.01).The plasma levels of lactate significantly increased in fish exposed to 5 and 15 μg/l Pb (NO3) and then declined to initial levels in treatment, 25 μg/l Pb (NO3) (P < 0.01). The plasma levels of TCA cycle intermediates significantly elevated in treatments 15 and 25 μg/l Pb (NO3) (P < 0.01). As a biomarker of oxidative stress, the plasma levels of malondialdehyde (MDA) showed significant increases in Pb (NO3) exposed fish (P < 0.01). During exposure period, wide ranges of liver tissue damages were also observed in Pb (NO3) exposed fish. In conclusion, exposure to Pb (NO3) affected the metabolome content of blood in grey mullet, mainly through inducing the biochemical pathways related to the metabolism of the amino acids, energetic metabolites and methylated metabolites. Our results may help to understand the effects of heavy metals on fish hematology from a molecular point of view.