Abstract: Objective To explore the effect of aripiprazole combined with agomelatine on depression, sleep quality and neurotransmitters in depression patients. Methods A total of 102 depression patients in Yingcheng Rongjun Hospital were enrolled. According to the random number table method, they were divided into two groups (n=51). The control group was treated with agomelatine, while the observation group was treated with aripiprazole combined with agomelatine. Both groups were compared for therapeutic effect, depression mood Hamilton Depression Scale (HAMD) score, and Montgomery-Asberg Depression Rating Scale (MARDS) score, Pittsburgh Sleep Quality Index (PSQI), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score, neurotransmitter index glutamate (Glu), γ-aminobutyric acid (GABA), serotonin (5-HT), norepinephrine (NE), acetylcholine (Ach), and dopamine (DA), nerve factor S100β protein (S100β), and brain-derived neurotrophic factor (BDNF) and Treatment Emergent Symptom Scale (TESS) scores before and after treatment. Results The observation group showed a higher total effective rate than the control group (P<0.05). The HAMD and MARDS scores of the observation group were lower than those of the control group after two, four, and six weeks of treatment (P<0.05). After two, four, and six weeks of treatment, the observation group presented decreases in Glu, and increases in NE, Ach, DA, 5-HT, and GABA, compared with the control group (P<0.05). The observation group showed lower serum S100β and higher BDNF than the control group after two, four, and six weeks of treatment (P<0.05). The observation group produced a higher PSQI score than the control group after six weeks of treatment (P<0.05). After six weeks of treatment, language, spatial structure, immediate memory, delayed memory, and attention scores increased in the observation group, compared with those in the control group (P<0.05). There was no statistical difference in TESS scores between the two groups after two, four and six weeks of treatment (P>0.05). Conclusions Aripiprazole combined with agomelatine is effective for the treatment of depression, which can enhance therapeutic effects, adjust the level of neurotransmitters, improve neurological function, improve the quality of sleeping, and relieve symptoms of depression.