Objective The aim was to evaluate the role of ursodeoxycholic acid (UDCA) on neonatal indirect hyperbilirubinemia treated with phototherapy. Background Hyperbilirubinemia is a common neonatal problem. The present study aimed to investigate the role of UDCA on neonatal hyperbilirubinemia treated with phototherapy. Participants and methods This randomized controlled clinical trial was conducted on 100 full-term neonates with unconjugated hyperbilirubinemia, who received phototherapy in the neonatal ICU of Menoufia University Hospital, and they were randomly divided into two groups: group 1, which is the case group (n = 50), received ursofalk (250 mg capsule) in dose of 10 mg/kg/day divided every 12 h with phototherapy, and group 2, which was the control group (n = 50), received only phototherapy. Total serum bilirubin levels measured every 24 h till phototherapy were disrupted. The duration of phototherapy was measured. Results The mean total bilirubin level measured at 24, 48, 72, and 96 h of treatment in group I was 13.6 ± 1.47, 10.9 ± 1.19, 9.13 ± 0.74, and 7.00 ± 0.14, respectively, and in group II was 14.5 ± 1.63 at 24 h, 12.2 ± 2.34 at 48 h, 10.5 ± 1.35 at 72 h, and 9.42 ± 0.82 at 96 h. Moreover, the mean duration of phototherapy was 65.2 ± 12.8 h in group I and was 82.5 ± 19.4 h in group II, showing high significant reduction in group I (P Conclusion Addition of oral UDCA to phototherapy in treatment of indirect hyperbilirubinemia will be highly effective and the duration of phototherapy and admission of affected newborns will be shorter.