Abstract: BACKGROUND: Hyperbilirubinemia is a common problem in neonates. The aim of this study was to evaluate the effect of synbiotic in addition to routine phototherapy on the treatment of neonatal jaundice. METHOD: This double-blind clinical trial, was performed on 194, 3–14 days old neonates. Neonates were divided into intervention and placebo groups. The intervention group received 5 drops of oral synbiotic daily along with phototherapy and the placebo group underwent phototherapy plus a placebo. Gestational age, age, weight, sex, initial and daily bilirubin level, frequency of defecation, mode of delivery, and length of hospitalization were assessed. RESULTS: The rate of bilirubin reduction on the first day of admission was significantly higher in the intervention group (2.9±1.81 vs. 2.06±1.93, p = 0.002). The mean level of bilirubin on the second (9.8±1.92 vs. 10.88±2.26) and third days (8.06±1.54 vs. 9.86±1.7) was lower in the intervention group (p = 0.001). The proportion of discharged patients in the third and fourth days was higher in the intervention group compared to the control (65% vs. 41%, 99% vs. 86.5%, respectively, p = 0.001). However, the duration of hospitalization was shorter in the intervention group compared to the control (2.36±0.5 vs. 2.74±0.74, p = 0.001). CONCLUSION: Based on our results, daily treatment with 5 drops of synbiotic along with phototherapy can be a safe and effective modality in faster bilirubin reduction, decreasing the hospitalization period and phototherapy. Therefore, it seems that it can be used as an adjunct therapy for neonates with jaundice.