Background: To compare the efficacy and safety of the combined application of both drain-clamping and tranexamic acid (TXA) versus the single use of either application in patients with total-knee arthroplasty (TKA). Methods: Databases (EMBASE, PubMed, Cochrane Library, Web of Sciences, the Google database, and the Ovid database) were searched from their inception through April 2018 for randomized controlled trials (RCTs) comparing the combined application of both drain-clamping and TXA versus single use of either application in patients with TKA. The Cochrane risk of bias (ROB) tool was used to assess the methodologic quality. The primary outcomes were blood loss in drainage, total blood loss, transfusion rate, and hemoglobin decline. The secondary outcomes were postoperative complications, the Knee Society Score (KSS), and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score. The statistical analysis was performed with RevMan 5.3.5 software. Results: A total of five RCTs (479 participants) were included in our meta-analysis. The present meta-analysis indicated that significant differences existed in the total blood loss (mean difference [MD] = -145.86, 95% confidence interval [CI]: -228.64 to -63.08, P = .0006), blood loss in drainage (MD = -169.06, 95% CI: -248.56 to -89.57, P < .0001), hemoglobin decline (MD = -0.66, 95% CI: -1.00 to -0.33, P = .0001), and transfusion rate (MD = 0.44, 95% CI: 0.26-0.75, P = .002) between the groups. However, regarding postoperative complications, no significant differences were found between the 2 groups in the KSS and the WOMAC score (P > .05). Conclusion: Combined application of both drain-clamping and TXA was associated with significant reductions in blood loss in drainage, total blood loss, hemoglobin decline, and the need for transfusion. However, high-quality, well-designed RCTs with long-term follow-up are still required.