Triclosan (TCS) is a ubiquitous antimicrobial used in many daily consumer products. It has been reported to induce endocrine disrupting effects at low doses in mammals, disturbing sex hormone function and thyroid function. The hypothalamus plays a crucial role in the maintenance of neuroendocrine function and energy homeostasis. We speculated that the adverse effects of TCS might be related to the disturbance of metabolic processes in hypothalamus. The present study aimed at investigating the effects of TCS exposure on the protein and metabolite profiles in hypothalamus of mice. Male C57BL/6 mice were orally exposed to TCS at the dosage of 10 mg/kg/d for 13 weeks. The hypothalamus was isolated and processed for mass spectrometry (MS)-based proteomics and metabolomics analyses. The results showed that a 10.6% decrease (P = 0.066) in body weight gain was observed in the TCS exposure group compared with vehicle control group. Differential analysis defined 52 proteins and 57 metabolites that delineated TCS exposed mice from vehicle controls. Among the differential features, multiple proteins and metabolites were found to play vital roles in neuronal signaling and function. Bioinformatics analysis revealed that these differentially expressed proteins and metabolites were involved in four major biological processes, including glucose metabolism, purine metabolism, neurotransmitter release, and neural plasticity, suggesting the disturbance of homeostasis in energy metabolism, mitochondria function, neurotransmitter system, and neuronal function. Our results may provide insights into the neurotoxicity of TCS and extend our understanding of the biological effects induced by TCS exposure.