Despite advances in research, critical gaps remain in understanding the molecular mechanisms of antipsychotic medications such as olanzapine. This study investigated the molecular pathways by which olanzapine exerts its therapeutic effects and causes metabolic side effects by analyzing changes in the serum metabolic and lipid profiles of patients with first-episode schizophrenia.Clinical symptoms were assessed using the Positive and Negative Symptom Scale (PANSS) in 43 patients with first-episode schizophrenia. Body mass index (BMI) and fasting glucose (GLU) and tetraplex lipids levels were measured before and after treatment. Changes in patient serum metabolic and lipid profiles before and after treatment were examined. Correlation analysis was used to identify differential metabolites and lipid molecules that were significantly associated with changes in clinical symptoms and metabolic side-effect indicators.After 8 weeks of olanzapine treatment, there was a significant decrease in all PANSS scores and a significant increase in BMI and GLU, total cholesterol, and low-density lipoprotein cholesterol levels in patients with first-episode schizophrenia. Metabolomic and lipidomic analyses identified 70 metabolites and 67 lipids in the serum that changed significantly after treatment. Correlation analysis revealed that the clinical symptom changes in the patients before and after treatment were significantly associated with 11 metabolites (most related to inflammation and oxidative stress), while the metabolic side-effect indicators were significantly associated with 14 lipid molecules.Olanzapine may improve psychotic symptoms by modulating inflammation and oxidative stress-related metabolites; however, olanzapine may also cause metabolic disturbances by affecting lipid metabolic pathways.Copyright © 2025 Elsevier B.V. All rights reserved.