Objective: To compare the effectiveness of blonanserin and olanzapine in the treatment of first-episode schizophrenia, so as to provide the basis for the medication choice for the treatment of first-episode schizophrenia. Methods: A total of 98 patients with first-episode schizophrenia admitted to the Second People's Hospital of Taizhou City were selected and randomly divided into the olanzapine group and the blonanserin group for a treatment period of two months. The Positive and Negative Syndrome Scale (PANSS), Pittsburgh Sleep Quality Index (PSQI), MATRICS Consensus Cognitive Battery (MCCB) were used to investigate the improvement of symptoms, sleep quality and cognitive function before and after treatment, respectively, and the level of prolactin was detected. The generalized estimation equation was used to compare the differences between the two groups. The adverse reactions of the two groups were recorded and the safety of medication was evaluated. Results: Forty-nine patients each group were included, with 29 males and a mean age of (37.22±7.17) years in the olanzapine group, and 27 males and a mean age of (37.54±7.31) years in the blonanserin group. There were no significant differences in gender, age, disease course and educational duration between the two groups (all P>0.05). The scores of positive symptom, negative symptom, general psychopathology and overall PANSS in the two groups after treatment were decreased compared with those before (all P<0.05). However, there was no significant difference between the two groups, and no interaction between the drugs and treatment duration (all P>0.05). The MCCB score of the blonanserin group was higher than that of the olanzapine group, while the PSQI score and the prolactin level of the blonanserin group were lower than that of the olanzapine group, and there was an interaction between the drugs and treatment duration (all P<0.05). The incidence of adverse reactions in the blonanserin group was 6.12%, which was lower than that in the olanzapine group of 20.41% (P<0.05). Conclusion Either blonanserin or olanzapine can improve psychotic symptoms inpatients with first-episode schizophrenia, while blonanserin is more effective than olanzapine in improving sleep quality, cognitive function and reducing prolactin level, and has higher safety.