Research on new serum parameters in bipolar disorder (BD) and schizophrenia is crucial for early diagnosis and understanding of disease pathophysiology. The arginine metabolic pathway has been found to be associated with several neuropsychiatric disorders in recent years. This study aims to investigate the role of serum markers involved in different steps of the arginine metabolic pathway in BD and schizophrenia. Sixty healthy volunteers, sixty patients with schizophrenia and sixty patients with BD were included in the study. We analysed ornithine decarboxylase (ODC), arginine decarboxylase (ADC) and agmatinase levels using enzyme-linked immunosorbent assay. Enzymatic colorimetric methods were used for nitric oxide (NO), nitric oxide synthase (NOS) and arginase measurement. Serum agmatinase levels were significantly lower in BD and schizophrenia (p < 0.01). ODC and ADC levels were significantly lower in BD group compared to the control and schizophrenia groups (p < 0.001; p < 0.01). Serum NO levels were significantly higher and NOS levels were significantly lower in BD (p < 0.001; p < 0.05). Arginase levels were also lower in BD (p < 0.05). Enzymes and substrates of the arginine metabolic pathway are promising markers in BD and schizophrenia. These markers can also be used to enable the diagnosis, when an adequate verbal communication is impossible.