Background Multiple doses of dexamethasone and tranexamic acid can inhibit postoperative inflammation and reduce fibrinolysis and perioperative blood loss in total knee arthroplasty. In this single-center, double-blind, randomized clinical trial, the aim was to investigate whether applying a tourniquet to patients on dexamethasone and tranexamic acid could further reduce perioperative blood loss. Materials and methods Patients who underwent cemented total knee arthroplasty at our hospital were randomized to receive a tourniquet (n = 71) or not (n = 70) during the procedure. All patients received multiple doses of dexamethasone and tranexamic acid perioperatively. The primary outcome was perioperative blood loss, while secondary outcomes were surgery duration, postoperative laboratory indices of inflammation and fibrinolysis, range of knee motion, VAS pain score, knee circumference, knee swelling rate, homologous transfusion, albumin use, and complications. Results Using a tourniquet was associated with significantly lower intraoperative blood loss (P < 0.001) and total blood loss (P = 0.007) as well as significantly shorter surgery duration (P < 0.001). In contrast, the tourniquet did not significantly affect hidden blood loss, postoperative inflammation or fibrinolysis, range of knee motion, VAS pain score, knee circumference, knee swelling rate, homologous transfusion, albumin use, or complications. Conclusions The results of this randomized clinical trial demonstrate that applying a tourniquet during cemented total knee arthroplasty to patients receiving multiple doses of dexamethasone and tranexamic acid can further reduce perioperative blood loss without increasing the risk of inflammation, fibrinolysis, or other complications. Thus, it is advised to use tourniquets combined with dexamethasone and tranexamic acid to reduce perioperative blood loss and avoid tourniquet-related adverse events. Level of evidence: Therapeutic Level I. Trial registration Chinese Clinical Trail Registry, ChiCTR2200060567. Registered 5 June 2022—retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=171291.