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The purpose of this systematic review and meta-analysis was to assess the preventive effect of theophylline on acute kidney injury and the ameliorative effect of theophylline on renal function in asphyxiated neonates. A literature search of the PubMed/Medline, Embase, and Cochrane Library databases for information published up to February 2019 was conducted. All studies that reported the incidence rate of acute kidney injury, serum creatinine level, and glomerular filtration rate after the randomized administration of theophylline or placebo were included. In total, eight studies involving 498 neonates were eligible. The incidence rate of acute kidney injury was significantly lower in the theophylline group than in the placebo group (risk ratio [RR]: 0.42, 95% confidence interval [CI]: 0.32-0.55, p < 0.001). The changes in serum creatinine level in the theophylline group were significantly higher than those in the placebo group from the first day of life to 3 and 5 days of age (weighted mean difference [WMD]: -0.51, 95% CI: -0.62 to -0.40, p < 0.001, and WMD: -0.26, 95% CI: -0.34 to -0.18, p < 0.001, respectively). The changes in glomerular filtration rate in the theophylline group were significantly higher than those in the placebo group from the first day of life to 3 days of age and the last day of follow-up (WMD: 12.30, 95% CI: 9.39-15.21, p < 0.001, and WMD: 9.35, 95% CI: 6.43-12.27, p < 0.001, respectively). These results suggested that theophylline has a beneficial effect on the prevention of acute kidney injury in neonates with perinatal asphyxia.