Objective To compare the efficacy and safety of expectant management versus acetaminophen for early treatment of hemodynamically significant patent ductus arteriosus (hsPDA) in very preterm infants. Methods A prospective randomized controlled trial was conducted from April 2024 to November 2025, enrolling 99 very preterm infants aged 4 to 7 days diagnosed with hsPDA. Participants were randomly assigned to either the expectant management group (n=54), which received no drug intervention, or the acetaminophen group (n=45), which received oral acetaminophen at 15 mg/kg every 6 hours for 3 days. Rates of hsPDA persistence at 3-4 days post-enrollment (7-11 days of age), 14-17 days of age, and at discharge or 36 weeks of corrected gestational age were compared between the two groups. Additionally, total duration of respiratory support, serum levels of alanine aminotransferase and cystatin C, and incidences of oliguria, upper gastrointestinal bleeding, intraventricular hemorrhage, moderate to severe bronchopulmonary dysplasia (BPD) were compared. Results The acetaminophen group showed lower rates of hsPDA persistence at 3-4 days post-enrollment and at 14-17 days of age compared to the expectant management group (both P0.05). No significant differences were found between groups at discharge or 36 weeks of corrected gestational age in hsPDA persistence, total respiratory support duration, or incidences of oliguria, upper gastrointestinal bleeding, intraventricular hemorrhage, and moderate to severe BPD (all P0.05). The acetaminophen group exhibited higher serum alanine aminotransferase and cystatin C levels at 3-4 days post-enrollment, and lower hourly urine output within 4 days post-enrollment compared with the expectant management group (all P0.05). Smaller gestational age and assisted reproductive technology were independent risk factors for persistent hsPDA at 14-17 days of age (OR=8.569 and 7.092, respectively; P0.05), while acetaminophen use was an independent protective factor (OR=0.126, P0.05). Conclusions Early oral acetaminophen treatment in very preterm infants with hsPDA aged 4-7 days reduces the rate of persistent hsPDA at 14-17 days and demonstrates a favorable safety profile compared with expectant management, but does not affect hsPDA persistence at discharge or 36 weeks of corrected gestational age or the rate of moderate to severe BPD.