Abstract: Objective To evaluate the short-term efficacy and safety of irbesartan/hydrochlorothiazide combined with recombinant human brain natriuretic peptide (rhBNP) for acute heart failure (AHF). Methods A total of 82 patients with AHF admitted to Beijing Rehabilitation Hospital, Capital Medical University from October 2022 to September 2023 were enrolled and randomly divided into a control group and a study group, with 41 cases in each group. The control group received irbesartan/hydrochlorothiazide, while the study group was additionally treated with rhBNP on the basis of the control regimen. The two groups were compared in terms of short-term clinical efficacy, Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score, cardiac function parameters, heart rate variability, 24-hour urine output and changes in immune function. Adverse drug reactions were also recorded. Results The study group had a significantly higher total response rate than the control group (P < 0.05), accompanied by shorter hospital stay and shorter time to symptom relief, lower APACHE Ⅱ score, and longer 6-minute walking distance (P < 0.05). Furthermore, the study group achieved superior outcomes in 24-hour urine output, left ventricular ejection fraction (LVEF) and heart rate variability indexes, as well as decreased left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) relative to the control group (P < 0.05). After 14 days of treatment, CD4⁺ levels and the CD4⁺/CD8⁺ ratio increased whereas CD8⁺ levels declined in both groups versus baseline (P < 0.05). No intergroup differences in these immune parameters were found at day 14 between the two groups (P > 0.05). No significant difference in the incidence of adverse drug reactions was detected between groups (P > 0.05). Conclusion Irbesartan/hydrochlorothiazide combined with rhBNP can effectively improve cardiac function and heart rate variability in patients with AHF, featuring favorable safety and promising clinical application value.