BACKGROUND: The aim of this research was to characterize changes in peripheral blood neurotransmitter metabolites in olanzapine-treated schizophrenia (SCZ) and to identify potential biomarkers for SCZ. Concurrently, the relationship between these differential neurotransmitters and cognitive function is explored. METHODS: We recruited 40 SCZ treated with single-agent olanzapine and 40 healthy controls (HC). Cognitive function and psychopathology were assessed using the MCCB and PANSS, respectively. Neurotransmitter levels were determined by targeted metabolomics approach using liquid chromatography-mass spectrometry (LC/MS). RESULTS: SCZ showed cognitive impairment in all domains of the MCCB compared to HC. Interestingly, a 4-neurotransmitter panel consisting of 3-Methoxytyramine hydrochloride (3-MT), 3,4-Dihydroxyphenylacetate (DOPAC), arginine, and r-aminobutyric acid (GABA) illustrated the highest determinative score between SCZ and HC. Arginine was positively correlated with PANSS general psychopathology scores. 3-MT independently predicted the verbal learning scores only in SCZ, whereas GABA independently predicted the social cognition scores only. Furthermore, GABA independently predicted the working memory scores only in HC. CONCLUSIONS: The collective assessment of these four neurotransmitters (3-MT, DOPAC, arginine, and GABA) holds considerable promise as potential biomarkers for SCZ. Moreover, 3-MT and GABA may enhance our understanding of cognitive dysfunction in SCZ, particularly in areas of verbal learning and social cognitive dysfunction.