This study examined the effects of recombinant human brain natriuretic peptide (rhBNP) combined with tolvaptan on cardiac and renal function and serum inflammatory factors in patients with severe heart failure (HF). This retrospective study included 90 patients with severe HF who were treated at our hospital between January 2019 and August 2021. Patients treated with tolvaptan tablets were assigned to the control group, and those treated with rhBNP combined with tolvaptan were assigned to the observation group. Efficacy, cardiac function, levels of inflammatory factors, renal function, 6 minutes walking test, Minnesota Living with Heart Failure Questionnaire score, and adverse reactions were assessed. The curative effect (97.78% vs 77.78%) and improvement in cardiac function were greater in the observation group than in the control group (P < .05). Decreased levels of inflammatory factors were seen in both groups after treatment, and the levels of tumor necrosis factor-α, interleukin-33, and intercellular adhesion factor-1 in the observation group were lower than those in the control group (P < .05). The 6 minutes walking test was higher and the Minnesota Living with Heart Failure Questionnaire score was lower in the observation group compared with the control group (P < .05). The incidence of adverse reactions such as dry mouth, nausea, polyuria, hypotension, and headache in the observation group was lower than that in the control group (P < .05). In conclusion, for patients with severe HF, rhBNP combined with tolvaptan can improve cardiac function, alleviate symptoms of dyspnea, protect renal function, and reduce serum inflammatory factor levels when compared with tolvaptan alone.