Malnutrition and sarcopenia frequently affect patients with heart failure (HF), in which clinical outcomes and survival is decreased. Thus, appropriate nutritional screening and early nutrition support are highly recommended. Currently, nutritional support is not a standard of care in patients with HF, and the use of commercially available oral supplements (OSs) could provide an additional benefit to medical treatment in these patients. To compare the effect of the Mediterranean diet in combination with hypercaloric, hyperproteic OS in patients with HF. An open label, controlled clinical study in which patients were randomly assigned to receive a Mediterranean diet (control group) vs. hypercaloric, hyperproteic OS (intervention group) for twenty-four weeks. Thirty-eight patients were included; epidemiological, clinical, anthropometric, ultrasound (muscle echography of the rectus femoris muscle of the quadriceps and abdominal adipose tissue), and biochemical evaluations were performed. All patients received additional supplementation with vitamin D. Baseline malnutrition according to the GLIM criteria was observed in 30% of patients, while 65.8% presented with sarcopenia. Body cell mass, lean mass, and body mass increased in the intervention group (absolute increase of 0.5, p = 0.03, 1.2 kg, p = 0.03, and 0.1 kg, p = 0.03 respectively). In contrast, fat mass increased in the control group (4.5 kg, p = 0.05). According to the RF ultrasound, adipose tissue, muscle area, and circumference tended to decrease in the intervention group; it is probable that 24 weeks was too short a period of time for evaluating changes in muscle area or circumference, as previously observed in another group of patients. In contrast, functionality, determined by the up-and-go test, significantly improved in all patients (difference 12.6 s, p < 0.001), including the control (10 s improvement, p < 0.001) and the intervention group (improvement of 8.9 s, p < 0.001). Self-reported QoL significantly increased in all groups, from 68.7 ± 22.2 at baseline to 77.7 ± 18.7 (p = 0.01). When heart functionality was evaluated, LVEF increased in the whole cohort (38.7 ± 16.6 vs. 42.2 ± 8.9, p < 0.01); this increase was higher in the intervention group (34.2 ± 16.1 at baseline vs. 45.0% ± 17.0 after 24 weeks, p < 0.05). Serum values of NT-proBNP also significantly decreased in the whole cohort (p < 0.01), especially in the intervention group (p = 0.02). After adjusting by age and sex, nutritional support, baseline LVEF, NT-proBNP, and body composition parameters of functionality tests were not associated with mortality or new hospital admissions in this cohort. Nutritional support with hypercaloric, hyperproteic OS, Mediterranean diet, and vitamin D supplementation were associated with decreased NT-proBNP and improvements in LVEF, functionality, and quality of life in patients with HF, despite a significant decrease in hospital admissions.