The purpose of this review was to determine the comparative efficacy between systemic and topical routes of tranexamic acid administration, optimal doses and timings, and the safety considerations of its use. 28 randomized controlled trials comparing the efficacy and safety of tranexamic acid use after total knee arthroplasty were included in this systematic review. Findings revealed both systemic and topical administrations reduced blood loss after total knee arthroplasty without increasing the incidence of symptomatic deep-vein thrombosis and pulmonary embolism.