Background: Total knee arthroplasty (TKA) is a common surgical procedure for treating end-stage knee osteoarthritis. However, excessive blood loss and postoperative pain are significant concerns. Objectives: To compare the efficacy of intravenous (IV) versus topical with IV tranexamic acid (TXA) and Bupivacaine in reducing perioperative blood loss and pain after TKA. Methods: This prospective, randomized study included 70 patients undergoing unilateral TKA. Patients were randomized into two groups with 35 patients in each group: IV TXA (Group 1) and IV plussubperiosteal administration of TXA and Bupivacaine cocktail (Group 2). The primary outcomes were change in hemoglobin levels and postoperative pain assessed using Visual Analog Scale (VAS) scores. Results: The results showed that Group 2 had lower drain collection and required fewer blood transfusions compared to Group 1. The IV+Subperiosteal group maintained higher hemoglobin levels throughout the study period. Additionally, Group 2 consistently showed lower VAS scores compared to Group 1 at all timepoints, indicating reduced pain levels. Conclusion: The study demonstrates that topical cocktail with IV TXA is more effective than IV TXA alone in reducing perioperative blood loss and pain after TKA. The findings suggest that topical cocktail of TXA and Bupivacaine can enhance the efficacy of IV TXA in reducing blood loss and pain.