Objective To explore the influence of amisulpride tablets on the sleep quality and quality of life of schizophrenia patients with mainly negative symptoms. Methods: 70 schizophrenia patients with mainly negative symptoms who were admitted to the psychiatry department of our hospital from May 2023 to April 2025 were selected as the research subjects. The research subjects were divided into the control group (35 cases) and the study group (35 cases) by the random number table method. The control group was treated with risperidone combined with cognitive behavioral therapy. The research group adopted cognitive behavioral therapy combined with oral amisulpride tablets for treatment. The sleep quality [Pittsburgh Sleep Quality Index (PSQI) score], quality of life [Schizophrenia Quality of Life Scale (SQLS-R4) score], negative symptoms [Negative Symptom Scale (SANS score)] and neurotransmitters [glial neurotrophic factor (GDNF), serotonin and brain-derived neurotrophic factor (BDNF)] of the two groups were analyzed and compared. Results: After 8 weeks of treatment, the PSQI scores of sleep quality, sleep onset time, sleep duration, sleep efficiency, sleep disorders, hypnotic drugs, and daytime function in both groups were significantly lower than those before treatment, and the PSQI scores of the study group were significantly lower than those of the control group (P < 0.05). After 8 weeks of treatment, the SQLS-R4 scores of each dimension including psychosocial function, physical function, symptom distress and life satisfaction in both groups were significantly lower than those before treatment, and the SQLS-R4 scores of each dimension in the study group were significantly lower than those in the control group (P < 0.05). After 8 weeks of treatment, the SANS scores of each dimension including emotional apaence, poor thinking, reduced willpower, social withdrawal and attention disorder in both groups were significantly lower than those before treatment, and the SANS scores of each dimension in the study group were significantly lower than those in the control group (P < 0.05). After 8 weeks of treatment, the levels of GDNF, 5-hydroxytryptamine and BDNF in both groups were significantly higher than those before treatment, and the levels of GDNF, 5-hydroxytryptamine and BDNF in the study group were significantly higher than those in the control group (P < 0.05). Conclusion: Amisulpride tablets can improve the sleep quality and quality of life of schizophrenia patients with mainly negative symptoms, alleviate negative symptoms, and improve the levels of neurotransmitters.