Background: The drilling technique used to make a femoral tunnel is critically important for determining outcomes after anterior cruciate ligament (ACL) reconstruction. The 2 most common methods are the transtibial (TT) and anteromedial (AM) techniques. Purpose: To determine whether graft orientation and placement affect clinical outcomes by comparing clinical and radiological outcomes after single-bundle ACL reconstruction with the AM versus TT technique. Study Design: Systematic review; Level of evidence, 3. Methods: Articles in PubMed, EMBASE, the Cochrane Library, ISI Web of Science, Scopus, and MEDLINE were searched from inception until April 25, 2020, using the following Boolean operators: transtibial OR trans-tibial AND (anteromedial OR trans-portal OR independent OR three portal OR accessory portal) AND anterior cruciate ligament. Results: Of 1270 studies retrieved, 39 studies involving 11,207 patients were included. Of these studies, 14 were clinical, 13 were radiological, and 12 were mixed. Results suggested that compared with the TT technique, the AM technique led to significantly improved anteroposterior and rotational knee stability, International Knee Documentation Committee (IKDC) scores, and recovery time from surgery. A higher proportion of negative Lachman ( P = .0005) and pivot-shift test ( P = .0001) results, lower KT-1000 arthrometer maximum manual displacement ( P = .00001), higher Lysholm score ( P = .001), a higher incidence of IKDC grade A/B ( P = .05), and better visual analog scale score for satisfaction ( P = .00001) were observed with the AM technique compared with the TT technique. The AM drilling technique demonstrated a significantly shorter tunnel length ( P = .00001). Significant differences were seen between the femoral and tibial graft angles in both techniques. Low overall complication and revision rates were observed for ACL reconstruction with the AM drilling technique, similar to the TT drilling technique. Conclusion: In single-bundle ACL reconstruction, the AM drilling technique was superior to the TT drilling technique based on physical examination, scoring systems, and radiographic results. The AM portal technique provided a more reproducible anatomic graft placement compared with the TT technique.