The extended use of thromboprophylaxis with direct oral anticoagulants (DOACs) for more than 30 days has been evaluated as an alternative for the standard duration thromboprophylaxis (7–10 days) with low molecular weight heparin in medically ill patients to reduce the risk of venous thromboembolism (VTE) after hospital discharge. EMBASE and MEDLINE were searched for studies evaluating extended duration thromboprophylaxis with DOACs versus standard thromboprophylaxis with enoxaparin in medically ill patients through October 2018. Search was limited to randomized-controlled trials. Symptomatic VTE, VTE-related death, and death from any cause, and major and clinically relevant non-major bleeding were used to assess the efficacy and safety, respectively. The Mantel–Haenszel random-effects model risk ratio (RR) and corresponding 95% CIs were calculated using the metan routine in Stata (version 14.2) to estimate the pooled treatment effects. Heterogeneity was assessed by the I2 statistics. Four studies met the inclusion criteria. DOACs were superior to enoxaparin in preventing symptomatic VTE (RR = 0.59, 95% CI 0.44–0.79). There were no significant differences in thromboprophylactic efficacy between extended and standard thromboprophylaxis as to VTE-related death (RR = 0.81, 95% CI 0.60–1.10) and death from any cause (RR = 0.98, 95% CI 0.87–1.09). Compared to the standard duration, extended thromboprophylaxis was associated with approximately two-fold greater risk of major (RR = 1.95, 95% CI 1.25–3.04), and clinically relevant non-major (RR = 1.81, 95% CI 1.29–2.53) bleeding. The superior efficacy was diminished by the unfortunate safety profile. Therefore, we continue to support both the American Society of Hematology (ASH) and the American College of Chest Physicians (ACCP) guidelines recommendation against the extended use of thromboprophylaxis beyond the hospital stay.