The novel direct oral anticoagulants (DOACs) have been proposed as alternatives to low-molecular-weight heparins (LMWHs) for the prevention of venous thromboembolism in orthopedic surgery. However, the clinical impact of postsurgical bleeding with the DOACs has not been extensively evaluated. MEDLINE and EMBASE databases, supplemented with conference abstract books and www.clinicaltrial.gov, were searched up to the first week of March 2015. We included phase II and phase III randomized controlled trials comparing the DOACs with LMWHs in patients undergoing major orthopedic surgery. Data regarding major, fatal, and intracranial bleeding were collected, to calculate the pooled relative risk (RR) and the case-fatality rate (CFR), with 95% confidence interval (CI). We retrieved 25 studies (5 evaluating dabigatran, 4 apixaban, 6 edoxaban, and 10 rivaroxaban), enrolling 42,170 patients. There was no significant difference between the DOACs and LMWHs in the risk of major (1.23 vs. 1.16%; RR: 1.07, 95% CI: 0.89–1.29), fatal (0.02 vs. 0.01%; RR: 1.63, 95% CI: 0.39–6.77), and intracranial bleeding (0 vs. 0.01%; RR: 0.33, 95% CI: 0.03–3.18). The weighted mean CFR of major bleeding was 3.3% (95% CI, 1.5–5.7) and 2.3% (95% CI, 0.7–4.6), respectively. Bleeding complications and the associated CFR during prophylactic anticoagulation in orthopedic surgery were very low and not significantly different between the DOACs and LMWHs.