Objectives: Post-dural Puncture Headache (PDPH) is prevalent among individuals undergoing lumbar punctures. The non-invasive effect of some drugs, such as aminophylline on PDPH has been investigated in several clinical studies. As there is no comprehensive systematic review and meta-analysis about the preventive and therapeutic effects of aminophylline on PDPH in the literature, the clinical effectiveness of this drug on the prevention and/or treatment of PDPH will be assessed in this study. Methods: PubMed/MEDLINE, Embase, WoS (Clarivate Analytics), the Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL Complete, Scopus, and Google Scholar as electronic databases will be precisely searched for clinical studies that assessed the effect of aminophylline on PDPH. Studies between 01-01-1980 and 30-06-2020 will be evaluated in this study, and there will not be any language restrictions. Contradictions between the reviewers within any phase of the study (screening, selecting, quality assessment, and data extraction) will be resolved by consensus; in case of unsolved disagreements, a third reviewer will eventually decide. The combination method will be applied according to the methodological resemblance in the selected articles using the Random Effect Model or the Fixed Effect Model. Also, for the included articles, forest plots will be drawn. For assessing statistical heterogeneity, the I2 statistic and the Q-statistic test will be applied. In addition, funnel plots will be used for assessing non-significant study effects and potential reporting bias. Furthermore, Egger’s and Begg’s tests will be done, and publication bias will be indicated by significant findings (P < 0.05). Conclusions: It is expected that the results of this study will be of benefit to researchers and clinicians for managing PDPH, and will be reported in conferences and publications.