Objective To compare the efficacy and safety between duloxetine and citalopram in the treatment of chronic heart failure (CHF) with depression and anxiety. Methods A total of 65 patients meeting the inclusion criteria were randomly divided into study group (n=29) and control group (n=28). The study group received conventional anti-heart failure treatment plus duloxetine, and the control group received conventional anti-heart failure treatment plus citalopram for 8 weeks. The two groups were evaluated using patient health questionnaire-9 (PHQ-9) and general anxiety disorder-7 (GAD-7). Patients were monitored for cardiac function, ALT, AST, Cr, BP, HR and other safety indicators before and after treatment. SPSS statistics 24.0 was used for statistical analysis. χ² test or Fisher exact probabilities method was employed for comparison of numeration data and t test or repeated measurement variance analysis for measurement data. Results Intra-group comparison found that the scores of PHQ-9 and GAD-7 at each time point were different after treatment (P<0.01) and tended to decrease with time. Comparison between groups found that the changes of PHQ-9 and GAD-7 at each time point were significantly different after treatment (P<0.05), the decrease of PHQ-9 and GAD-7 at each time point in study group was greater than that in control group. After treatment, there was no significant difference in cardiac function between the two groups (P>0.05). There was no significant difference in safety indicators before and after treatment in each group (P>0.05). Conclusion Duloxetine outperformed citalopram in the treatment of depression and anxiety, and their effect on cardiac function was similar. Duloxetine, with good safety, can be used in CHF patients with depression and anxiety.