Patients with sickle cell disease (SCD) experience initial and recurrent venous thromboembolism (VTE) more commonly and at a younger age than the general population, and it confers a higher mortality for patients with SCD. However, limited evidence is available to guide anticoagulant use for VTE treatment in this population. The primary objective of this study is to characterize the effectiveness and safety of direct oral anticoagulants (DOAC) and warfarin for VTE treatment among patients with SCD. This single-center retrospective study includes adult patients with SCD who were diagnosed with VTE. Data was obtained from review of electronic health records for the 6 months after VTE diagnosis. Among the 22 patients treated initially with a DOAC, 6 (27%) developed recurrent VTE, none experienced major bleeding, and 3 (14%) experienced clinically relevant non-major bleeding (CRNMB). Similarly, of 15 patients initially treated with warfarin, 3 (20%) developed a recurrent VTE, 1 (7%) experienced major bleeding, and 2 (13%) experienced CRNMB. Twelve patients received more than one oral anticoagulant during the study period, most commonly due to a recurrent VTE, concern for non-adherence, or subtherapeutic INR. Overall, the incidence of VTE recurrence and bleeding events were similar between groups, but occurred at a higher rate than those found in major clinical trials of anticoagulant agents. Prescribers should continue to individualize therapeutic decision-making regarding oral anticoagulant therapy for VTE treatment for individuals with SCD based on patient-specific factors and anticipated ability to adhere to the drug regimen or required monitoring.