Recent evidence suggests that expectant management of hemodynamically significant patent ductus arteriosus (PDA) may confer better outcomes. To assess clinical outcomes of active treatment vs expectant management of hemodynamically significant PDA in preterm infants. The PubMed (MEDLINE), Embase, and Cochrane Library databases were searched for randomized clinical trials (RCTs) published between January 1, 2010, and July 31, 2024. RCTs were included if they enrolled preterm infants born before 33 weeks of gestation and had 2 groups comparing active treatment with expectant management. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement was followed. Data were extracted by 2 independent reviewers. The Cochrane Risk of Bias tool was used to assess study quality. A random-effects model was used to estimate the pooled effects. The primary outcomes were a composite of death at 36 weeks' postmenstrual age or at discharge (whichever occurred later) or moderate to severe bronchopulmonary dysplasia (BPD), death at 36 weeks, and moderate to severe BPD. Secondary outcomes included intraventricular hemorrhage, periventricular leukomalacia (PVL), retinopathy of prematurity, and necrotizing enterocolitis. This meta-analysis included 10 RCTs involving 2035 infants. There were 1018 infants in the active treatment group (510 female [50.1%]) and 1017 infants (551 male [54.2%]) in the expectant management group. The mean (SD) gestational age was 26.2 (1.7) weeks vs 26.3 (1.7) weeks, and the mean (SD) birth weight was 874.7 (222.1) g vs 897.7 (216.5) g, respectively. The incidence of the composite outcome (death at 36 weeks or at discharge or moderate to severe BPD) was higher in the active treatment group vs the expectant management group (516 of 918 [56.2%] vs 465 of 915 [50.8%]; relative risk [RR], 1.10 [95% CI, 1.01-1.19]; P = .02). Deaths at 36 weeks were higher in the active treatment group (139 of 974 [14.3%] vs 109 of 969 [11.2%]; RR, 1.27 [95% CI, 1.01-1.61]; P = .04). There were nonsignificant increases in moderate to severe BPD (372 of 785 [47.4%] vs 349 of 806 [43.3%]; RR, 1.08 [95% CI, 0.95-1.23]; P = .25) and PVL (52 of 913 [5.7%] vs 32 of 908 [3.5%]; RR, 1.50 [95% CI, 0.98-2.30]; P = .06) in the active treatment group vs the expectant management group. This meta-analysis found that active treatment of hemodynamically significant PDA during the first 2 weeks of life was associated with a significantly higher incidence of death or moderate to severe BPD and with increased mortality compared with an expectant management approach. Further research is needed for revision of protocols for PDA management.