Venous thromboembolism (VTE) is a potentially fatal complication of hospitalization. Thromboprophylaxis using subcutaneous low molecular weight heparin (LMWH) can result in local irritation, pain, and ecchymoses, leading to nonadherence. Direct acting oral anticoagulants (DOACs) are an alternative, but their efficacy and safety for short-term inpatient-only use versus LMWH, in medically hospitalized patients, has not been rigorously assessed. We performed a systematic review with meta-analyses and exploratory cost effectiveness analysis of Phase III randomized controlled trials comparing DOACs to LMWH for VTE prophylaxis to determine the risk and benefit of each. The primary efficacy end point (composite of total VTE and any-cause mortality) occurred in 1,321 of 10,978 (11.4%) of patients receiving DOAC prophylaxis and 1,084 of 10,600 (10.2%) with LMWH (odds ratio [OR] 0.84; 95% confidence interval [CI] 0.63 to 1.13). The primary safety end point (composite of major bleeding and clinically relevant bleeding) occurred in 519 of 16,131 (3.2%) of patients receiving DOACs and 381 of 14,616 (2.6%) with LMWH (OR 1.12; 95%CI 0.83 to 1.53). Subgroup analyses for efficacy (n = 9,233) and safety (n = 12,584) was conducted on patients randomized to Apixaban or LMWH. The primary efficacy end point occurred in 294 of 4618 (6.4%) patients on Apixaban and 383 of 4615 (8.3%) on Enoxaparin (OR 0.82; 95% CI 0.55 to 1.24). Major and clinically relevant bleeding occurred in 157 of 6278 (2.50%) and 185 of 6,306 (2.9%), respectively (OR 0.86; 95% CI 0.58 to 1.26). Exploratory cost effectiveness analysis suggested that Apixaban compared with Enoxaparin thromboprophylaxis could result in long-term cost savings. In conclusion, this systematic review of randomized controlled trials and meta-analysis, stratified by type of patients and drug, indicates noninferiority of DOACs in efficacy, safety, and cost for short-term VTE thromboprophylaxis among patients hospitalized for medical illness.