To investigate differences of metabolites in serum and urine between patients with both anti-N-methyl-D-aspartic acid receptor (NMDAR) encephalitis and mental disorder before and after clozapine treatment. Methods: Total 18 patients with anti-NMDAR encephalitis and mental disorder (patients group) and 18 healthy individuals (control group) were enrolled. Patients were treated with clozapine until clinical symptoms disappeared. The Positive and Negative Syndrome Scale (PANSS), modified Rankin Scale (mRS), and Clinical Global Impression (CGI) scale were used to evaluate mental status, neurological function, and drug efficacy in patients. Ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was used to analyze metabolites in serum and urine. Changes in and patterns of endogenous metabolites in the serum and urine of both groups were analyzed by metabonomics technology combined with multivariate statistical methods. The receiver operating characteristic (ROC) curve was used to further explore the reliability of biomarkers in clinical diagnosis and the therapeutic effect of clozapine in patients. Results: PANSS score, mRS score, and CGI score of the patients group were significantly lower after treatment than that before treatment (P<0.05). The results of metabonomic analysis showed that 11 and 9 different metabolites were identified in the serum and urine of patients group, respectively. The ROC curve analysis of serum and urine data showed that glutamine, taurine, and gamma-aminobutyric acid (GABA) provided certain accuracy in diagnosis. Seven different metabolites and 6 different metabolites were identified in the serum and urine of patients before and after treatment, respectively. The ROC curve showed that taurine and glycine could be used as metabolites related to the efficacy of clozapine. Conclusion: Glutamine, taurine, and GABA can be used as candidate biomarkers for diagnosis in patients with anti-NMDAR encephalitis combined with mental disorder. Taurine and glycine can be used as candidate biomarkers to evaluate drug efficacy after treatment.