Introduction The SARS-CoV-2 is a human pathogenic coronavirus that causes a respiratory tract infection, which may lead to systemic hyper-inflammation that is associated with a hypercoagulable state. Anticoagulation as an adjunct may decrease thrombi formation. Objectives This study aims to evaluate the efficacy and safety of enoxaparin for the prevention of thrombotic events in hospitalized SARS-CoV-2 patients with elevated D-dimer. Methods A single-center retrospective cohort study was conducted to evaluate three enoxaparin dosing regimens: full treatment (1 mg/kg SC Q12H or 1.5 mg/kg SC Q24H), intermediate (.5 mg/kg SC Q12H or 1 mg/kg SC Q24H), and prophylaxis (40 mg SC Q24H). The primary endpoint evaluated the percentage of patients who developed a venous thromboembolism (VTE). The secondary endpoints evaluated the development of a major bleed, mechanical ventilation need, and death. Results Forty-five patients were included with 27, 8, and 10 participants in the full treatment, intermediate, and prophylaxis arms, respectively. Six patients developed a VTE: 3, 1, and 2 in the listed above groups, respectively ( P = .83). Twenty patients died: 11, 3, and 6, respectively ( P = .64). Four patients developed a major bleed: 1, 1, and 2, respectively ( P = .17). Six patients required intubation: 1, 2, and 3 in the arms, respectively ( P = .043). Conclusion The study did not find a difference in respect to the development of a VTE between the three investigated doses of anticoagulation. However, our findings suggest that treatment dose of enoxaparin might be associated with lower risk for mechanical ventilation in hospitalized COVID-19-positive patients with elevated D-dimer.