Objective To investigate the therapeutic effects of vericiguat in combination with recombinant human brain natriuretic peptide in patients with heart failure with reduced ejection fraction (HFrEF). Methods Seventy patients with HFrEF were enrolled and randomly divided into study group (n=35) and control group (n=35). The control group received conventional treatment for HFrEF, while the study group was treated with vericiguat and recombinant human brain natriuretic peptide in addition to the conventional treatment. Left ventricular ejection fraction (LVEF), left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), amino-terminal brain natriuretic peptide precursor (NT-proBNP), 6-min walking distance as well as resting heart rate, systolic blood pressure and diastolic blood pressure were compared between the two groups before and after treatment. Adverse reactions during treatment were also compared between the two groups. Results After treatment, LVEF in two groups was significantly higher than before treatment, and the study group was significantly higher than that in the control group (P < 0.05). After treatment, the LVESD, LVEDD, NT-proBNP as well as resting heart rate, systolic blood pressure and diastolic blood pressure in the two groups were significantly lower than before treatment, and the study group was significantly lower than the control group (P < 0.05). After treatment, the 6 min walking test distance of two groups was significantly longer than that before treatment, and the study group was significantly longer than the control group (P < 0.05). There was no significant difference in the occurrence of adverse reactions between the two groups (P>0.05). Conclusion Vericiguat combined with recombinant human natriuretic peptide can effectively improve cardiac function in HFrEF patients with few adverse reactions.