Sickle Cell Disease (SCD) is the most common genetic disease in the United States. Symptoms result from formation of sickle hemoglobin (HbS), which polymerizes and obstructs vasculature. Voxelotor, a HbS polymerization inhibitor, was granted accelerated approval by the Food and Drug Administration in 2019 for chronic treatment of SCD. While voxelotor may offer a disease-modifying approach to SCD, little is known about long-term safety profile. Venous thromboembolism (VTE) is a potential adverse effect (AE) that rarely occurred during clinical trials. While pulmonary embolism (PE) is listed as a potential AE, the pathophysiologic mechanism has yet to be elucidated. We report a patient with SCD presenting to the emergency department (ED) with acute onset shortness of breath, tachycardia, and hypotension in the setting of newly initiated voxelotor twenty days prior to arrival. Computed tomography pulmonary angiography showed multiple acute subsegmental PEs. Lower extremity doppler showed acute bilateral DVTs. Voxelotor, which was suspected to have provoked the VTEs, was discontinued indefinitely. The patient's reaction scored a 5 on the Naranjo Adverse Drug Reaction Probability Scale, indicating probable causal relationship between the VTEs and voxelotor. Although listed as an AE on its drug label, the only reports of voxelotor-associated VTE are in the results of clinical trials. To our knowledge, we present the first case of VTE likely provoked by voxelotor. While voxelotor offers a promising therapeutic option for SCD, emergency medicine physicians should be aware of severe AEs that may necessitate ED visits.