Objective To investigate the efficacy and safety of rivaroxaban in prevention of lower limb venous thrombosis after total knee arthroplasty in the elderly. Methods A total of 356 patients underging total knee arthroplasty in Liaocheng Second People′s Hospital from March 2017 to March 2018 were randomly divided into the control group and study group (n=178 each). The control group were given low-molecular-weight heparin to prevent venous thrombosis, and the study group were given rivaroxaban to prevent lower limb venous thrombosis. The two groups were compared in the incidence of deep venous thrombosis in the lower limbs, hemorrhage, and death within one year after operation. Changes of inflammatory factors [tumor necrosis factor α(TNF-α), interleukin-6 (IL-6), IL-1β] and coagulation parameters [(D-Dimer, fibrinogen (FIB), activated partial thromboplastin (APTT), prothrombin time (PT), thrombin time (TT), platelet (PLT)] were also compared between two groups before and after treatment. Data analysis was performed using GraphPad Prism 5.0. The t test or χ² test was used for comparison between the two groups. Survival analysis was estimated by Kaplan-Meier method and Log-rank test. Results Compared with before treatment, TNF-α, IL-6, IL-1β, PLT, D-Dimer and FIB were significantly decreased in the elderly patients after knee arthroplasty (P<0.05), while APTT, PT and TT were significantly increased (P<0.05). The D-Dimer of the study group was significantly lower than that of the control group (P<0.05). After 1 year, the incidence of deep venous thrombosis in the lower limbs was significantly lower in the study group than in the control group (χ²=5.838, P=0.016). Adverse reaction occurred in 2 cases(1.12%) of the study group and 19 cases (10.67%) of the control group with statistically significant difference (χ²=8.865, P=0.003). The 1-year survival rate of the study group was significantly higher than that of the control group (χ²=4.614, P=0.032). Conclusion Rivaroxaban outperformed low-molecular-weight heparin in the efficacy and safety in the prevention of lower limb venous thrombosis after total knee arthroplasty in the elderly, and its mechanism may be related to the inhibition of inflammatory response.