Growing evidence suggests that heart failure (HF) is associated with an increased risk of depressive disorders and anxiety. However, the existing studies were observational and may have confounded and not reflected true causal relationships. This study collected genetic instruments about HF, depression, and anxiety from publicly available genetic summary data. Two-sample Mendelian randomization (MR) analysis was performed, with inverse-variance weighted designated as the primary approach for determining causal effects. Secondary analyses included MR-Egger regression and the weighted media method. Additionally, we conducted MR pleiotropy residual sum and outlier to address horizontal pleiotropy. Cochran Q test, MR-Egger intercept test, and leave-one-out analysis were used to assess the robustness of the findings. The significance is determined by a P-value below .05. Gene prediction result revealed that HF did not exhibit a significant association with elevated incidence of depression by inverse-variance weighted method no matter HF from the Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium (odds ratio [OR] = 1.05, 95% confidence interval [CI] = 0.93-1.18, P = .424 for major depressive disorder, MDD; OR = 1.01, 95% CI = 0.94-1.09, P = .782 for major depression) or the FinnGen Consortium (OR = 1.03, 95% CI = 0.92-1.15, P = .644 for MDD; OR = 1.00, 95% CI = 0.94-1.07, P = .962 for major depression). In contrast, the results of HF on anxiety exhibited inconsistency (OR = 1.60, 95% CI = 1.10-2.31, P = .013 for Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium; OR = 1.42, 95% CI = 0.91-2.21, P = .123 for FinnGen Consortium); however, a combined effect analysis indicated support causal relationship between HF and the risk of anxiety (OR = 1.52, 95% CI = 1.07-2.00, P < .001). Our findings did not reveal evidence to confirm a causal association between HF and depression. However, our results provide support for a causal effect of HF on the risk of anxiety., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)