Venous thromboembolism (VTE) remains an important complication after total knee arthroplasty (TKA). Systemic thrombin generation starts perioperatively. Inflammation, characterized by a rise in interleukin-6 (IL6), initiates the coagulation cascade, but low-dose steroids can reduce post-TKA IL6 levels. This double-blinded, randomized, placebo-controlled study enrolled 30 patients undergoing unilateral TKA to assess the effect of perioperative steroids on serum prothrombin fragment (PF1.2), a marker of thrombin generation, and plasmin-alpha-2-antiplasmin complex (PAP), a marker of fibrinolysis. Study patients received 100 mg of intravenous hydrocortisone 2 h prior to surgery, and controls received normal saline. Blood samples, drawn pre-incision and at 4 h post tourniquet release, were assayed for PF1.2 and PAP. The study group had significantly lower mean PF1.2 at 4 h compared to controls (616 ± 358 pMol/L vs. 936 ± 332 pMol/L, p = 0.037). The mean rise in PF1.2 in the control group was significantly greater compared to the study group (672 ± 173 pMol/L vs. 350 ± 211 pMol/L, p < 0.001). Mean PAP was higher in the study group at 4 h (1639 ± 823 µg/L vs. 1087 ± 536 µg/L), but did not reach statistical significance (p = 0.07). These results may have clinical implications in terms of postoperative VTE risk and management.