Background One of the most common complications of cancer chemotherapy is oral mucositis (OM). OM affects more than 75% of patients undergoing chemotherapy and represents a significant burden to patients and caregivers. We performed a systematic review and meta­analysis of published studies to investigate the effects of agents and techniques in reducing OM. Procedure This systematic review investigated, critically appraised, and rated the evidence on agents used to manage OM in children undergoing cancer therapy. A comprehensive search of the relevant literature was performed from January 2006 to December 2017. MEDLINE, Scopus, the Cochrane Database of Systematic Reviews, EMBASE, and the Web of Science were searched. Nine eligible studies were identified. Using random­effects models, standardized mean difference was estimated between treated and control groups across all studies. The Cochran test and the I2 index were performed for heterogeneity between studies. The significance level was set at P = 0.05. Results Palifermin reduced the incidence (OR = 4.131, P = 0.000), duration (St diff mean = 0.803, P = 0.000), and severity (St diff mean = 0.637, P = 0.000) of OM in pediatric cancer patients significantly. However, the laser did not show significant efficacy in decreasing the incidence rate of OM (OR = 2.870, P = 0.364). Conclusion This review provided a comprehensive examination of available options for children who have OM. The results support the possibility of a positive effect of palifermin on reducing OM in children receiving cancer therapy.