Introduction: The concept of maintaining apical patency (AP) is a controversial issue in endodontics. The primary objectives of this systematic review of randomized controlled trials (RCTs) were to determine the influence of maintaining AP during instrumentation on postoperative pain severity and the prevalence of flare-ups. A second objective was to assess the effect of maintaining AP on the use of analgesics. Methods: RCTs and controlled clinical trials were searched for in MEDLINE (Ovid), Embase (Ovid), and the Cochrane Library. Four reviewers independently screened all identified articles for eligibility. The included studies were assessed for bias using the Cochrane Risk of Bias Tool. The Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the quality of the body of evidence. Because of the considerable heterogeneity of the studies, a meta analysis was not possible. Therefore, the results were analyzed narratively. Results: Five RCTs that included a total of 848 patients were found eligible and included in the review. An assessment of the risk of bias in the included studies provided results that classified the studies as showing a low risk (n = 1), high risk (n = 1), or unclear risk (n = 3) of bias. The available evidence indicated that maintaining AP (1) did not increase postoperative pain in teeth with nonvital pulp, (2) did not increase postoperative pain in teeth with vital pulp, and (3) did not cause (0%) flare-ups. The available evidence also indicated that maintaining AP did not increase analgesic use. The available evidence indicated that maintaining AP did not increase postoperative pain when a single-visit or 2-visit root canal treatment approach was used. Conclusions: In light of the current evidence, maintaining AP does not increase postoperative pain in teeth with vital/nonvital pulp when compared with nonapical patency (low to moderate quality evidence). Furthermore, maintaining AP did not cause flare-ups (low evidence) and did not increase analgesic use (moderate evidence).