Direct oral anticoagulants (DOACs) are an emerging treatment option for cancer patients with acute venous thromboembolism (VTE), but studies have reported inconsistent results. This systematic review and meta-analysis compared the efficacy and safety of DOACs and low-molecular-weight heparins (LMWH) in these patients. MEDLINE, Embase, CENTRAL, and conference proceedings were searched to identify relevant randomized controlled trials. Additional data were obtained from the original authors to homogenize definitions for all study outcomes. The primary efficacy and safety outcomes were recurrent VTE and major bleeding, respectively. Other outcomes included the composite of recurrent VTE and major bleeding, clinically relevant non-major bleeding (CRNMB), and all-cause mortality. Summary relative risks (RR) were calculated in a random effects meta-analysis. In the primary analysis comprising 2,607 patients, the risk of recurrent VTE was non-significantly lower with DOACs than with LMWH (RR 0.68; 95% CI, 0.39 to 1.17). Conversely, the risks of major bleeding (RR 1.36; 95% CI, 0.55 to 3.35) and CRNMB (RR 1.63, 95%, 0.73 to 3.64) were non-significantly higher. The risk of the composite of recurrent VTE or major bleeding was non-significantly lower with DOACs than with LMWH (RR 0.86; 95% CI, 0.60 to 1.23). Mortality was comparable in both groups (RR 0.96; 95% CI, 0.68 to 1.36). Findings were consistent during the on-treatment period and in those with incidental VTE. In conclusion, DOACs are an effective treatment option for cancer patients with acute VTE, although caution is needed in patients at high risk of bleeding.