Abstract Background Total knee replacement (TKR) is a very common operation to deal with advanced osteoarthritis to relieve pain and disability. Undergoing TKR may necessitate allogenic blood transfusion and patients remain concerned about the potential serious complications of transfusion. tranexamec acid (TXA), antifibrinolytic which can minimise the need for blood transfusion. Objective To assess the therapeutic importance and side effects of tranexamic acid and the use of drain in TKR and to conduct a systematic review and meta-analysis of what has been published about this topic. Patients and Methods This is a systematic review study and meta-analysis on human subjects studied in different literatures collected from different medical websites up to August 2022 that dealing with the therapeutic importance and side effects of tranexamic acid and the use of drain in TKR. The study was performed in the Orthopedic Surgery Department, Faculty of Medicine, Ain Shams University along the period from December 2021 to August 2022. Results The study showed that the incidence of females was more than that of males; 53.65% and 17.03% in TXA group, respectively and 6.897% and 22.45% in non-TXA group, respectively. The total incidence was 70.65% in TXA group and 29.35% in non-TXA group. The study showed that the mean ages were 66.15 ± 4.53 and 67.98 ± 5.91 y in TXA and drain groups, respectively with insignificant difference. The mean weights were 64.98 ± 3.24 and 67.79 ± 5.198 Kg in TXA and drain groups, respectively. The mean BMI was 26.89 ± 1.99 26.72 ± 1.49 kg/m2 in the two groups, respectively. Data Sources Medline databases (PubMed, Medscape, ScienceDirect. EMF-Portal) and all materials available in the Internet till 2023. Conclusion Tranexamic acid is effective and safe in reducing blood loss, the requirement for blood transfusion, and drain output in patients undergoing knee arthroplasty with less total postoperative complications.