Objective To investigate the therapeutic effects of varying treatment durations of recombinant human brain natriuretic peptide （rhBNP） on heart failure following percutaneous coronary intervention （PCI） in patients with acute ST-segment elevation myocardial infarction （STEMI）. Methods A total of 196 STEMI patients with heart failure （HF） following emergency percutaneous coronary intervention （PCI） were enrolled and randomly assigned to one of four groups： control group （n = 53）， short-course rhBNP group （n = 47）， medium-course rhBNP group （n = 50）， and long-course rhBNP group （n = 46）. The rates of cardiovascular mortality and HF-related rehospitalization were evaluated at 30 days and 6 months post-treatment. Serum levels of N-terminal pro-B-type natriuretic peptide （NT-proBNP）， matrix metalloproteinase-9 （MMP-9）， tissue inhibitor of matrix metalloproteinase-1 （TIMP-1）， left ventricular end-diastolic diameter （LVEDD）， and left ventricular ejection fraction （LVEF） were measured at 24 hours， 3 days， 1 week， 30 days， and 6 months after HF treatment initiation. Results Compared with the control group， both the short- and medium-term rhBNP groups showed a significant reduction in cardiovascular mortality and HF-related rehospitalization rates in the long-term rhBNP group at 30 days and 6 months （P < 0.05）. Additionally， the medium-term rhBNP group exhibited lower HF-related rehospitalization rates than both the control and short-term rhBNP groups （P < 0.05）. Serum levels of NT-proBNP， MMP-9， and LVEDD significantly decreased in the short-term rhBNP group within 24 hours compared to the control group （P < 0.05）， while TIMP and LVEF levels increased （P < 0.05）. In comparison with the short-term rhBNP group， the medium-term rhBNP group demonstrated sustained reductions in NT-proBNP， MMP-9， and LVEDD levels at 72 hours， 1 week， 30 days， and 6 months （P < 0.05）， accompanied by increases in TIMP and LVEF （P < 0.05）. Furthermore， the long-term rhBNP group showed greater improvements than the medium-term group， with significantly lower NT-proBNP， MMP-9， and LVEDD levels and higher TIMP and LVEF values at 1 week， 30 days， and 6 months （P < 0.05）. In terms of the adverse reactions， the incidence of hypotension in the control group， short course rhBNP group， medium course rhBNP group and long course rhBNP group increased successively （P < 0.05）. Conclusion The clinical efficacy of rhBNP in STEMI patients with HF following PCI gradually improved as the treatment duration increased， but the incidence of hypotension also rose accordingly.