25 randomized controlled trials (RCTs) investigating the safety of direct oral anticoagulants and low molecular weight heparin/fondaparinux in antithrombotic prophylaxis during total hip replacement, total knee replacement, and hip fracture surgery were included. This meta-analysis was conducted in order to determine if direct oral anticoagulants, in addition to the more convenient oral administration and potentially increased compliance rates, are able to provide an enhanced safety profile. The findings of this systematic review and meta-analysis demonstrated comparable risks of major, fatal, and intracranial bleeding, and comparable case-fatality rate between groups.