Triclosan (TCS), an extensively used antimicrobial agent, has raised considerable concern due to its hepatocarcinogenic potential. However, previous hepatotoxicity studies primarily focused on the activation of specific intracellular receptors, the underlying mechanisms still warrant further investigation at the metabolic level. Herein, we applied metabolomics in combination with lipidomics to unveil TCS-related metabolic responses in human normal and cancerous hepatocytes. Endogenous and exogenous metabolites were analyzed for the identification of metabolic biomarkers and biotransformation products. In L02 normal cells, TCS exposure induced the up-regulation of purine metabolism and amino acid metabolism, caused lipid accumulation, and disturbed energy metabolism. These metabolic disorders in turn enhanced the overproduction of reactive oxygen species (ROS), leading to the alteration of antioxidant enzyme activities, down-regulation of endogenous antioxidants, and peroxidation of lipids. TCS-induced oxidative stress is thus considered to be one crucial factor for hepatotoxicity. However, in HepG2 cancer cells, TCS underwent fast detoxification through phase II metabolism, accompanied by the enhancement of energy metabolism and elevation of antioxidant defense system, which contributed to the potential effects of TCS on human hepatocellular carcinoma development. These different responses of metabolism between normal and cancerous hepatocytes provide novel and robust perspectives for revealing the mechanisms of TCS-triggered hepatotoxicity.