Background: Post-dural puncture headache (PDPH) is one of the most common complications in patients undergoing spinal anesthesia. The present systematic review and meta-analysis aimed to assess the therapeutic and prophylactic effects of aminophylline and theophylline on PDPH. Methods: Relevant studies were identified by searching the following electronic databases, without language restriction, until June 2020: Scopus, EMBASE, MEDLINE, Google Scholar, Web of Science, Cochrane Library-CENTRAL, and CINAHL Complete. Random effects models were used to calculate the standardized mean difference (SMD) and risk ratios (RRs) with 95% confidence intervals (95% CI) to assess the therapeutic and prophylactic effects of aminophylline and theophylline on PDPH, respectively. The Cochrane tool was used for the quality assessment of the included studies. The certainty of the evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation method. Results: Of the 1,349 initial records, 15 met our eligibility criteria (6 studies on therapeutic and 9 on prophylactic effects). A significant reduction in the pain score was observed following aminophylline/theophylline treatment (SMD = –1.67; 95% CI, –2.28 to –1.05; P < 0.001, I2 = 84.7%; P < 0.001). Subgroup analysis revealed that the therapeutic effect was significantly higher when these agents were compared to placebo than when conventional therapies were used. The risk of PDPH after aminophylline administration was not significantly reduced (RR = 0.74; 95% CI, 0.42 to 1.31; P = 0.290). Conclusions Theophylline and aminophylline have therapeutic, but not prophylactic, effects on PDPH.