Total knee arthroplasty (TKA) is amenable to various regional anesthesia techniques that may improve patient outcome. We sought to answer whether regional anesthesia decreased mortality, cardiovascular morbidity, deep venous thrombosis and pulmonary embolism, blood loss, duration of surgery, pain, opioid-related adverse effects, cognitive defects, and length of stay. We also questioned whether regional anesthesia improved rehabilitation. To do so, we performed a systematic review of the contemporary literature comparing general anesthesia and/or systemic analgesia with regional anesthesia and/or regional analgesia for TKA. To reflect contemporary surgical and anesthetic practice, only randomized, controlled trials from 1990 onward were included. We identified 28 studies involving 1538 patients. There was insufficient evidence from randomized, controlled trials alone to conclude if anesthetic technique influenced mortality, cardiovascular morbidity other than postoperative hypotension, or the incidence of deep venous thrombosis and pulmonary embolism when using thromboprophylaxis. Our review suggests there was no difference in perioperative blood loss or duration of surgery in patients who received general anesthesia versus regional anesthesia. Compared with general anesthesia and/or systemic analgesia, regional anesthesia and/or analgesia reduced postoperative pain, morphine consumption, and opioid-related adverse effects. Length of stay may be reduced and rehabilitation facilitated for patients undergoing regional anesthesia and analgesia for TKA.