Background: Venous thromboembolism (VTE) is a common complication that manifests during and/or after hospitalization, as well as postsurgeries including orthopedic surgeries. Edoxaban is a new oral direct factor Xa inhibitor that has been recently approved for treating VTE in patients who have already been treated with a parenteral anticoagulant and for the prevention of stroke and non-central nervous system systemic embolism in patients with nonvalvular atrial fibrillation. Objectives: The purpose of this systematic review was to evaluate the safety and efficacy of edoxaban for VTE prophylaxis after lower limb orthopedic surgery. Materials and Methods: A comprehensive search was conducted in Google Scholar, PubMed, MEDLINE, and ScienceDirect to identify potential records, then titles, abstracts, and full texts were screened using the inclusion criteria to filter out irrelevant studies. Moreover, the data extraction and quality assessment were undertaken using standardized tools, and the results were narratively synthesized and presented in tables. Results: Six studies were included in this systematic review after screening 2989 records. The majority of studies demonstrated a statistically significant reduction in VTE events in the edoxaban group(s) compared to the dalteparin, placebo, or enoxaparin groups (P.05). Conclusion: This study helped to amalgamate evidence with regard to the use of edoxaban for VTE prophylaxis post-lower limb orthopedic surgery. In line with the results of the reviewed studies, edoxaban seems to be highly effective in reducing VTE post-lower limb orthopedic surgery.