AbstractBackgroundWhile ursodeoxycholic acid is used in treating parenteral nutrition‐associated cholestasis (PNAC) in neonates, its role in prevention is unclear.ObjectivesIn this systematic review and meta‐analysis, we attempted to determine the role of ursodeoxycholic acid in preventing PNAC in neonates.MethodsPubMed, Embase, Cochrane Library, Scopus, and CINAHL databases were searched on September 16, 2023, for interventional studies comparing ursodeoxycholic acid with placebo.ResultsOf the 6180 unique records identified, five studies were eligible for inclusion (three randomised and two nonrandomised). Evidence from randomised trials showed that ursodeoxycholic acid prophylaxis did not reduce cholestasis, mortality, sepsis, and necrotising enterocolitis. Ursodeoxycholic acid prophylaxis reduced feed intolerance (RR 0.23 (0.09, 0.64); 1 RCT, 102 neonates), peak conjugated bilirubin levels (MD −0.13 (−0.22, −0.04) mg/dL; 1 RCT, 102 neonates), and time to full enteral feeds (MD −2.7 (−5.09, −0.31) days; 2 RCTs, 76 neonates). There was no decrease in hospital stay and parenteral nutrition duration. Data from nonrandomised studies did not show benefit in any of the outcomes. The certainty of the evidence was low to very low.ConclusionBecause of the very low‐quality evidence and lack of evidence on critical outcomes, definitive conclusions could not be made on using ursodeoxycholic acid to prevent parenteral nutrition‐associated cholestasis in neonates.