(1) Background: In recent years, "new" direct oral anticoagulants (DOAC) have gradually replaced other antithrombotic therapies. The international literature agrees on the increased mortality for traumatic brain injury (TBI) patients using vitamin K antagonists (VKA), but thus far, there are insufficient data on the influence of DOAC on the outcome of TBI. (2) Methods: We retrospectively analyzed data from all patients who presented with head trauma using antithrombotic therapy. Outcome parameters were the presence of pathologies on the initial CT, occurrence of delayed intracranial hemorrhage, surgical intervention, and death. (3) Results: In total, data of 1169 patients were reviewed. Of those, 1084 (92.7%) had a mild TBI, 67 (5.7%) moderate TBI, and 17 (1.5%) severe TBI. In total, 456 patients (39%) used DOAC and 713 patients (61%) used VKA, antiplatelet therapy, or prophylactic doses of low molecular weight heparin at the time of trauma. The groups showed no significant differences in age, injury mechanisms, or GCS at presentation. Overall, the initial cranial CT showed pathologies in 85 patients (7.3%). Twenty-five patients with head trauma and DOAC therapy had pathological findings on CT (5.5%), 11 patients with VKA (4.8%), and 48 patients with antiplatelet therapy (10.6%). There was a statistically significant difference in occurrence of CT pathologies between DOAC alone compared to acetylsalicylic acid (4.9 vs. 10.5%, p = 0.04). Delayed intracranial hemorrhage after an initially negative CT during in-hospital observation occurred in one patient (0.2%) in the DOAC group, two patients (0.9%) in the VKA group, and four patients (0.9%) in the antiplatelet group without statistical significance. Head trauma related surgery was performed in three patients (0.7%) in the DOAC group, two patients (0.9%) in the VKA group, and six patients (1.3%) in the antiplatelet group without statistical significance. Death due to head trauma occurred in four patients (0.9%) of the DOAC group compared to one patient (0.4%) of the VKA group and five patients (1.1%) of the antiplatelet group without statistical significance. (4) Conclusions: Our data suggest a comparable risk of pathological CT findings, delayed intracranial hemorrhage, surgical interventions, and death after blunt head trauma for patients with DOAC compared to VKA, but a lower risk for pathological CT findings compared to platelet inhibitors. As VKA are known to increase mortality, our data suggest that similar caution should be used when treating patients with head trauma and DOAC, but the overall numbers of serious or severe courses after simple falls remain low. We recommend routine CT for all head trauma patients with antithrombotic therapy but the role of in-hospital observation for patients with mild TBI remains a matter of debate.