Background <p>Schizophrenia is not well differentiated from bipolar disorder when acute psychiatric symptoms are present. Recently, several studies have suggested a potential link between unconjugated bilirubin and schizophrenia and bipolar disorder, but the exact relationship has not been elucidated.</p> Methods <p>To compare the levels of unconjugated bilirubin in the blood of patients with schizophrenia and bipolar disorder and to analyze whether there is a potential causal relationship between unconjugated bilirubin and schizophrenia and bipolar disorder using mendelian randomization, and finally to validate the relationship between them by the clinical symptoms and the levels of unconjugated bilirubin before and after MECT.</p> Results <p>Blood levels of unconjugated bilirubin were significantly higher(<i>P</i> = 0.0001) in schizophrenia (11.53 ± 5.442 µmol/L) than in bipolar disorder (9.063 ± 3.463 µmol/L). Unconjugated bilirubin levels in the blood of patients with schizophrenia in the acute phase were significantly higher than those of patients with bipolar disorder, and mendelian randomization analysis showed a significant causal relationship between unconjugated bilirubin and schizophrenia (OR = 1. 131, 95% CI: 1.034–1.237, <i>P</i> = 0.007). Patients with schizophrenia treated with MECT showed a significant reduction in clinical symptoms and a significant decrease in unconjugated bilirubin.</p> Conclusions <p>This study found that patients with schizophrenia had significantly higher unconjugated bilirubin levels compared to patients with bipolar disorder. Mendelian randomization results suggest a positive causal relationship between unconjugated bilirubin and schizophrenia. Decreases in unconjugated bilirubin after MECT alleviated clinical symptoms of schizophrenia. It provides a new idea for clinical diagnosis of schizophrenia and bipolar disorder.</p>