Chronic pain is a recognized complication of surgery, and it has been hypothesized that regional anesthesia might reduce the risk of development of chronic pain after upper extremity surgery. A systematic literature review was performed to assess whether in patients undergoing elective upper extremity surgery (P), regional anesthesia (I), compared to general anesthesia (C), would result in lower long-term (>3 months) postoperative pain intensity (O). We included randomized and nonrandomized controlled trials (RCTs). Our primary outcome was numerical rating score or visual analogue scale for pain, at >3 months postoperatively. The Embase, Medline ALL, Web of Science Core Collections, Cochrane Central Register of Controlled Trials, and Google Scholar databases were searched for all reports assessing pain at >3 months after upper extremity surgery under general versus regional anesthesia. Secondary outcomes were: opioid prescription filling, complex regional pain syndrome (CRPS) incidence, the Mayo Wrist Score (MWS), and scores on the Disability of the Arm, Shoulder and Hand (DASH) questionnaire. Quality (or certainty) of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Risk-of-bias was assessed using the Cochrane tool for randomized trials (RoB 2.0) and nonrandomized trials (ROBINS-I). This review included 14 studies, comprising 7 RCTs and 7 nonrandomized studies. Six of the 7 studies (4 RCTs, N = 273; 2 nonrandomized studies, N = 305) using a pain score, our primary outcome, report comparable long-term postoperative pain scores after regional and general anesthesia. Six of the 7 studies using our secondary outcomes report comparable long-term outcomes in terms of opioid prescription filling (2 retrospective cohort studies RCSs, N = 89,256), CRPS incidence (1 RCT, N = 301), MWS (1 RCT and 1 RCS, N = 215), and DASH score (1 RCT, N = 36). Comparable outcomes were reported in all 7 RCTs (N = 778) and in 5 of the 7 nonrandomized studies, comprising 5 RCSs (N = 89,608). Two prospective observational studies (POSTs), comprising 279 patients, report a statistically significant difference in outcomes, with less pain and better DASH scores after brachial plexus anesthesia. All 14 studies provided moderate to very low certainty evidence, and there was a serious risk of bias due to confounding bias in 5 of the 7 nonrandomized studies (N = 631). The results of this review indicate that upper extremity regional anesthesia, compared to general anesthesia, is unlikely to change pain intensity at >3 months postoperatively.