Vaso-occlusive crisis (VOC) in sickle cell disease can cause severe pain and requires a thoughtful approach to analgesia. Considering the heightened awareness of the harm associated with opioids, an exploration of safer and more effective alternatives is overdue. Ketamine may play a role in supplementing or replacing opioid analgesia for patients in VOC. Studies on the use of ketamine for VOC are sparse, though increasing. In this review, we summarize the literature on subdissociative ketamine use for VOC to offer providers insight into the most effective and safe dosing regimens for sickle cell disease patients. Overall, the studies discussed in this review show decreased opioid use when subdissociative ketamine is provided as an adjunct and resolution of pain for most patients when subdissociative ketamine is used as the sole form of analgesia in VOC. Most studies examined intravenous delivery, and successful outcomes were established for both adult and pediatric patients in multiple clinical settings, including in the emergency department. Although more research is needed, it is clear from the published data that subdissociative ketamine may provide an efficacious addition to the clinician’s toolbox for managing VOC.