Background: Hyperbilirubinemia is one of the most common and persistent problems encountered in preterm newborns. This condition in preterm infant is more likely to be associated with neurological damage rather than terms. So far, no major studies have precisely assessed the effects of zinc sulfate on hyperbilirubinemia in low-birth-weight (LBW) neonates. Therefore, in this study, we aimed to evaluate these effects in LBW infants. Methods: This randomized, double-blind, clinical trial (IRCT201401041162N22) was performed on 61 icteric LBW neonates, hospitalized in the neonatal intensive care unit (NICU) of Imam Reza Hospital in Mashhad, Iran from May 24, 2014 to May 24, 2015. The neonates were randomly divided into case and control groups, and the total serum bilirubin (TSB) level was measured at 0, 24, 48, 72, 96, and 120 h after treatment. The subjects received either 10 mg of zinc sulfate or placebo twice per day for five days (or by the end of treatment). The termination point of phototherapy was defined as a bilirubin level below 50% of the starting point. The collected data were analyzed, using SPSS version 20. Chi-square, t-test, and repeated measures ANOVA were carried out to compare the findings between the two groups. Results: The mean TSB level was 14.87±2.65 and 14.73±3.22 mg/dl in the control and case groups. The mean decline in TSB level was only significant at 24 h after the treatment (2.71 and 2.13 mg/dl in the case and control groups, respectively; P=0.04), while being statistically insignificant on other days of the assessment. Also, similar findings were reported regarding the duration of treatment in the case and control groups (58.84±14.97 and 65.60±16.59 h in the case and control groups, respectively). Conclusion: The present study showed that administration of oral zinc sulfate in icteric LBW infants could significantly reduce TSB level only at 24 h following the treatment.