Objective To evaluate the efficacy and safety of ibuprofen in treating hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants of different postnatal ages at treatment initiation. Methods Clinical records of infants with gestational age <37 weeks who received ibuprofen for hsPDA in the Department of Neonatology, Fourth Hospital of Shijiazhuang, from January 2020 to December 2023 were retrospectively reviewed. One hundred eligible infants were divided by the postnatal age at the first ibuprofen administration into three groups: group A (≤4 days), group B (5-7 days), and group C (>7 days). Clinical efficacy and safety indicators were compared among groups. Results After treatment, cure rates were 92% in group A, 72% in group B, and 60% in group C, and effective rates were 8%, 25%, and 33%, respectively. Differences in clinical efficacy among the three groups were statistically significant (P<0.05). No significant differences were observed among groups in the incidence of pulmonary hemorrhage, gastrointestinal bleeding, cholestasis, bronchopulmonary dysplasia, necrotizing enterocolitis, intracranial hemorrhage, or acute kidney injury (P>0.05). Conclusions For hsPDA requiring pharmacologic therapy, earlier oral ibuprofen administration yields a higher ductal closure rate and does not increase the incidence of adverse events.