Background: Anterior cruciate ligament (ACL) reconstruction can be performed with different techniques for independent and transtibial (TT) drilling of femoral tunnels, but there is still no consensus on which approach leads to the best outcome. Purpose: To assess whether the independent or TT drilling approach for ACL reconstruction leads to the best functional outcomes. Study Design: Systematic review; Level of evidence, 2. Methods: A systematic literature search was conducted on July 1, 2020, using the PubMed, Web of Science, Cochrane Library, and Scopus databases. The influence of different femoral drilling techniques was analyzed through a meta-analysis in terms of patient-reported outcome measure scores, risk of complications, range of motion limitations, graft failure, and differential laxity. Subanalyses were performed to compare the different independent drilling techniques considered. Linear metaregression was performed to evaluate if the year of study publication influenced the results. The risk of bias and quality of evidence were assessed following the Cochrane guidelines. Results: A total of 22 randomized controlled trials including 1658 patients were included in the meta-analysis. Both International Knee Documentation Committee (IKDC) subjective score and Lysholm score were higher with the independent drilling approach (mean difference [MD], 1.24 [ P = .02] and 0.55 [ P = .005], respectively). No difference was documented in terms of the risk of reinjury, but independent drilling led to reduced KT-1000 arthrometer–assessed anterior tibial translation (MD, 0.23; P = .01) and a higher probability of a negative postoperative pivot-shift test finding (risk ratio, 1.13; P = .04). There were no significant differences in IKDC objective or Tegner scores. A P value of .07 was found for the association between the year of the study and IKDC objective scores. Conclusion: Independent femoral tunnel drilling provided better results than the TT approach, although the difference was not clinically significant. No difference was observed in the risk of reinjury. Increasingly better results were seen among surgical procedures performed in more recent years. Among the independent drilling options, the anteromedial portal technique seemed to provide the most favorable outcomes. The lack of clinically significant differences and the promising outcomes reported with new modified TT techniques suggest the importance of correct placement, rather than the tunnel drilling approach, to optimize the results of ACL reconstruction.