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Background: Tranexamic acid (TXA) has been widely applied in total knee arthroplasty (TKA) to significantly reduce perioperative blood loss and improve knee function recovery in patients after surgery. The choice of antithrombotic agents for venous thromboembolism (VTE) prevention after TKA is controversial. Therefore, this study aimed to compare the effects of different antithrombotic agents on patients after primary unilateral TKA in the context of applied TXA., Methods: A total of 180 patients undergoing primary unilateral TKA from October 2020 to December 2021 were included in this study. All patients were given an intraoperative drip of 60 mg/kg TXA. Thereafter, patients were divided into three groups (n = 60 each). Baseline data were comparable among the three groups. The average follow-up time was 3.02 ± 0.09 months. Group 1 enrolled patients receiving oral rivaroxaban (RA) at 10 mg, Group 2 included patients who received subcutaneous Dalteparin sodium at 2500 IU, while Group 3 included patients taking oral aspirin (ASA) at 100 mg. Patients in all the three groups received treatment once a day for 30 days at 12 h postoperatively. The primary outcomes in this study were post-treatment drainage volume and thrombotic complication rate. The secondary outcomes included hematologic parameters, transfusion rate, intraoperative blood loss, total blood loss (TBL), and bleeding complication rate., Results: The average drainage volume after treatment was significantly lower in Group 3 than in Group 1 and Group 2 (205.2 ± 69.0 vs 243.4 ± 72.5 vs 295.4 ± 72.5 ml, P < 0.001), and there was a significant difference between Group 1 and Group 2 (243.4 ± 72.5 mL vs 295.4 ± 72.5 mL, P < 0.001). The blood transfusion rate of Group 2 dramatically increased compared with Group 1 and Group 3 (20.0% vs 6.7% vs 5.0%, P = 0.01). The bleeding complication rate in Group 1 apparently increased relative to Group 2 and Group 3 (26.7% vs 10.0% vs 8.3%, P = 0.008). Besides, there was no significant difference in the thrombotic complication rate among the three groups., Conclusion: Under the background of TXA application, ASA, RA, and Dalteparin sodium were all effective on preventing VTE after TKA. In addition, ASA effectively reduced post-treatment Hemoglobin (Hb) loss, drainage volume, TBL, transfusion rate, and bleeding complications compared with RA and Dalteparin sodium., Trial Registration: The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2200060169). Date of Registration: 21/05/2022., (© 2023. The Author(s).)