BACKGROUND: The painful procedures experienced by neonates during hospitalization have short-term or long-term effects on neonates. While the limitations of previous interventions make it imperative to explore effective interventions that are readily available. This systematic review and meta-analysis was conducted to evaluate the safety and effectiveness of massage for pain management in neonates. METHODS: This systematic review was registered in PROSPER. PubMed, Embase, Cochrane Library, and the Clinical Trials Registry were searched to December 2021. Two reviewers independently carried out study selection, data extraction, bias risk assessment. Continuous data were analyzed by mean differences (MD). Dichotomous data were reported using relative risk. If at least two studies reported identical results by the same pain assessment tool, a meta-analysis was conducted using random effect model and inverse variance. RESULTS: Total 11 included studies involving 755 neonates investigated the effects of massage on neonatal pain response compared to standard care. The meta-analysis showed that massage could effectively improve pain response in neonates compared to standard care no matter whether neonatal infant pain scale (NIPS) or premature infant pain profile (PIPP) was used as an assessment tool. Besides, massage was also effective for crying duration, blood oxygen saturation both during and after the procedure, but non-effective for the variation of respiratory rate after the procedure, and heart rate both during and after the procedure. CONCLUSIONS: Massage may have a positive effect on pain relief of neonate, and rigorous trials are needed in the future to determine the most effective massage method.