Objective To analyze the effects of flupentixol melitracen on plasma N-terminal pro-brain natriuretic peptide (NT-probNP) and B-type brain natriuretic peptide (BNP) levels and depressive mood of patients with coronary heart disease with heart failure complicated with depression. Methods A total of 88 patients with coronary heart disease with heart failure complicated with depression who were admitted to Liyang People's Hospital from July 2018 to October 2020 were divided into the control group and the experimental group according to the random number table method, with 44 cases in each group. Patients in the control group received conventional drugs combined with psychological intervention, and patients in the experimental group were treated with Flupentixol melitracen on the basis of the control group. Both groups were treated for 4 weeks. The clinical efficacy after treatment , plasma NT-proBNP and BNP levels, cardiac function index levels and depression before and after treatment of patients in the two groups were compared. Results After treatment, the total clinical effective rate of the experimental group was 93.18%, which was higher than 77.27% of the control group; compared with before treatment, after treatment, the plasma levels of NT-proBNP, BNP and the scores of Hamilton Depression Scale (HAMD), health questionnaire depression Scale-9 (PHQ-9) , self-rating depression scale (SDS) of patients in the two groups decreased, and the experimental group was lower than the control group; after treatment, the levels of LVEF of patients in the two groups increased, and the experimental group was higher than the control group; after treatment, the 6 minutes walking distance (6 MWD) of patients in the two groups were longer than before treatment, and the experimental group was longer than the control group (all P <0.05). Conclusion The application of Flupetixol melitracen in the treatment of patients with coronary heart disease with heart failure complicated with depression can increase the clinical efficacy, reduce myocardial load and myocardial injury, improve cardiac function, and can effectively relieve patients' depression with good therapeutic effect.