Background and objective <p>Obesity is common in heart failure (HF), worsening quality of life and depressive symptoms. While semaglutide, a GLP-1 agonist, aids weight loss in obese adults, its impact on health and mood in obese HF patients is unclear. This study evaluated semaglutide’s effects on body weight, health status, and mood in obese HF patients over one year. </p> Methods <p>A retrospective analysis was conducted on 122 obese HF patients treated consecutively with semaglutide between January 2019 and August 2023. The primary endpoints were changes in body mass index (BMI), Hospital Anxiety and Depression Scale (HADS) scores, and Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) from baseline to one year. Secondary endpoints included changes in NYHA functional class and NT-proBNP levels. </p> Results <p>Semaglutide treatment resulted in a significant weight reduction at one year, with a mean BMI decrease of −2.23 kg/m² (95% CI −2.71 to −1.75; p &lt; 0.001). This weight reduction was consistent across patients with baseline BMI &lt; 35 kg/m² and ≥ 35 kg/m² (p for interaction = 0.26). HADS anxiety scores decreased from a baseline of 5 points (IQR: 2–8) to 3 points (IQR: 1–7; p = 0.037), while HADS depression scores decreased from 6 points (IQR: 3–8) to 3 points (IQR: 1–6; p &lt; 0.001). KCCQ-OSS scores improved from 62 points (IQR: 52–77) at baseline to 82 points (IQR: 55–95; p &lt; 0.001) at one year. These improvements in HADS depression and KCCQ-OSS scores were consistent across all subgroups, including those with baseline LVEF (≥ 50% or &lt; 50%), BMI (≥ 35 kg/m² or &lt; 35 kg/m²), ischemic versus non-ischemic cardiomyopathy, and the presence or absence of diabetes. Additionally, significant improvements in NYHA class and NT-proBNP levels were observed at one year.</p> Conclusion <p>Semaglutide significantly improves health status and mood in obese heart failure patients, with these improvements strongly correlating with weight loss.</p> Graphical Abstract <p></p>