Background: Combining different drug classes is essential in the treatment of patients with heart failure, especially those with multiple comorbidities. However, this can increase the risk of drug-drug interactions. Objective: To investigate the characteristics of drug use and clinically relevant drug interactions in patients hospitalized for heart failure with reduced ejection fraction (HFrEF). Materials and methods: This study retrospectively reviewed all medical records of patients with HFrEF, treated at the Interventional Cardiology Department of a hospital in Can Tho City from January to December 2023. Drug interactions were assessed for daily prescribed medications, using three databases: the Ministry of Health's contraindicated drug interactions list, drugs.com, and medscape.com. Results: The study sample included 41 medical records (corresponding to 301 treatment days). The patients’ mean age was 66.27 ± 16.12 years; males 82.93%; and 100% with at least a comorbidity. Polypharmacy (≥5 drugs) occurred on 88.04% treatment days. Loop diuretics for congestive symptoms were the most prescribed drug class with 80.49% patients. Fundamental drug classes for heart failure involved mineralocorticoid receptor antagonists (MRAs) with 75.61% patients; SGLT2 inhibitors (SGLT2i) 53.66%; beta-blockers 48.78%; and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers 46.34%. Clinically relevant drug interactions occurred on 87.71% of total treatment days, with 53.82% considered severe and 83.06% moderate. The most common severe interactions concerned proton pump inhibitors, including rabeprazole–clopidogrel (22.59%); esomeprazole–clopidogrel (12.29%); and rabeprazole–digoxin (14.29%). No contraindicated-level interactions were observed. Conclusion: MRAs and SGLT2 inhibitors were the most commonly used fundamental drug classes. The rate of clinically relevant drug interactions—especially severe ones—remained high. This requires close monitoring to minimize adverse reactions for patients.