OBJECTIVE: This study aimed to evaluate the efficacy of paliperidone combined with sertraline in treating schizophrenia (SCZ) and its effect on serum neurofunctional factors. METHODS: A retrospective analysis was conducted on SCZ patients admitted between June 2020 and June 2021. Initially, 80 patients were treated with paliperidone, while 36 received a combination of paliperidone and sertraline. Propensity score matching based on 3 covariates resulted in 2 groups: the control group (paliperidone alone, n = 36) and the observation group (paliperidone + sertraline, n = 36). The clinical efficacy, adverse reactions, quality of life scores, serum biomarkers levels related to nerve and liver function, and anxiety and depression levels were compared between the 2 groups. RESULTS: The observation group demonstrated higher total effectiveness than the control group ( CONCLUSIONS: Paliperidone combined with sertraline effectively improves serum neuregulin levels in SCZ patients, alleviates negative emotional effects without causing liver or kidney damage, and demonstrates excellent clinical efficacy and safety.