Objective To explore the efficacy of probiotics combined with blue phototherapy on neonatal hyperbilirubinemia (NHB). Methods 120 cases of children patients with NHB in our hospital from January 2016 to March 2017 were divided into study group and control group according to the random number table method, with 60 cases in each group. The two groups were given blue phototherapy, and study group was added with probiotics on this basis. The efficacy of the two groups was observed. The levels of immune indexes [immunoglobulin G (IgG), immunoglobulin M (IgM) and T cell subsets (CD4+, CD4+/CD8+) were evaluated after 2 w of treatment, and the adverse drug reactions of children patients were recorded. Results The total effective rate in study group was higher than that in control group (P<0.05). After 2 w of treatment, the immune indexes in study group were higher than those in control group (P<0.05). The incidence rate of total adverse reactions in study group was lower than that in control group (P<0.05). Conclusion Probiotics combined with blue phototherapy is a safe and effective treatment regimen for NHB. Probiotics can reduce the risk of intestinal adverse reactions and enhance the immune function.