Disseminated intravascular coagulation (DIC) is a relatively rare but life-threatening condition, the outcome of which depends largely on timely and accurate therapeutic management. Inhibiting the activation of blood coagulation is an effective option for limiting the burden of diffuse intravascular thrombosis for attenuating consumption of clotting factors and platelets and ultimately preventing massive bleeding. Direct oral anticoagulants (DOACs) are a relatively new generation of drugs that specifically inhibit activated factors II (thrombin) and X, thus providing effective anticoagulation while concomitantly limiting the hemorrhagic risk compared with other conventional anticoagulant agents. The peculiar mechanism of action would hence at least theoretically support their usage in patients with DIC, especially in those with a more pronounced thrombotic phenotype. A comprehensive literature search on the use of DOACs in patients with intravascular coagulopathies currently yielded only 15 documents, all case reports, totaling 21 patients (dabigatran, n = 5; rivaroxaban, n = 13; apixaban, n = 3; edoxaban, n = 0). Taken together, the current literature data suggest that these drugs may have low prophylaxis efficacy and thereby their indication for preventing DIC in high-risk patients may be limited. Nevertheless, DOACs seem at least therapeutically equivalent to heparin in some forms of DIC, especially in those with prevalent thrombotic phenotype, while having more favorable oral administration. The inherent risk of hemorrhages from heparin injection is also shared by DOACs; therefore, their use in DIC patients with a prevalent bleeding phenotype will probably remain unwarranted. Major caution should also be used in patients with impaired drug metabolism, especially those progressing toward liver or renal failure or receiving aggressive antimicrobial treatment. Where potentially indicated, further clinical trials should be planned to test the therapeutic efficacy of these drugs in patients with different types or forms of DIC.