Purpose: Inflammation is reported to play an important part in mediating injury in neonatal hypoxic-ischemic encephalopathy (HIE). Whether inflammatory-related cytokine such as IL-6 and TNF-α is associated with risk of HIE remains unknown. Method: In this meta-analysis of 29 clinical trials published to date in Chinese VIP, Wangfang, CNKI, Pubmed, Google Scholar database using the keywords “IL-6”,“TNF-α” and “hypoxic-ischemic encephalopathy/HIE”, we selected eligible studies which met the inclusion criterion, extract interested information and analyzed outcomes using the Review Manage 5.3 software. Results: Meta-analysis including 1618 HIE newborns and 790 healthy controls showed that serum IL-6 was significant up-regulated in different states (mild, moderate, severe) of neonatal hypoxic-ischemic encephalopathy (HIE) with the value of IV was 2.62, 4.91, 6.55, 95% CI [2.03, 3.22],[4.01, 5.80],[5.46, 7.64] and P< 0.01. Similarly, compared to healthy controls, elevated serum TNF-α was also found to be associated with risk of neonatal HIE, the value of Std. Mean. Difference was 4.00, 4.75, 8.24, 95% CI was [3.60, 4.40],[4.07, 5.43],[7.38, 9.11] and P value< 0.01. Conclusion: Meta-analysis suggested that elevated serum IL-6 and TNF-α level in newborns is associated with high risk of hypoxic-ischemic encephalopathy (HIE)-induced brain injury. Further studies are needed to validate these observations.