Background Phototherapy is paramount in the management of high total serum bilirubin (TSB). Whether its effectiveness can be improved with ursodeoxycholic acid (UDCA) has not been evaluated among newborns of African descent. Methods A double-blind-controlled study was used to evaluate the effect of UDCA on the management of high TSB in neonates. Recruited neonates were categorized into the experimental group (given UDCA plus phototherapy) and the control group (phototherapy and plain syrup), and their TSB and conjugated bilirubin levels were measured. The data were analyzed using SPSS version 20. Statistical significance was set at a p -value of <0.05. Results The mean (SD) percentage reductions in TSB after 24 hrs were 40.73% (18.1) and 10.21% (7.1) in the experimental and control groups, respectively, and the difference was statistically significant ( p =0.001). The mean (SD) durations on therapy were 3.0 days (0.58) in the experimental group and 5.5 days (1.35) in the control group ( p =0.001). Conclusions Phototherapy is still effective in the management of neonatal hyperbilirubinemia, but inclusion of UDCA accentuates the reductive effect of phototherapy on the TSB in neonates, reducing the duration of treatment and in-patient care.