Background: Patients who develop sickle cell disease (SCD) nephropathy are at a high risk for mortality. The pathophysiology of vaso-occlusive pain crisis may contribute to acute kidney injury (AKI). Non-steroidal anti-inflammatory drugs, known inducers of AKI, are used to treat pain crises. Multiple gaps exist in the knowledge about the impact of AKI in SCD. Methods: We conducted a 2-year retrospective review of AKI events in patients admitted for vaso-occlusive crisis. AKI was defined by an increase of ≥0.3 mg/dL or 50% in serum creatinine from baseline. Laboratory values and ketorolac administration by days and dose (mg/kg) were identified from hospital records. A generalized mixed effects model for binary outcomes evaluated AKI based on laboratory variables and ketorolac administration. A generalized mixed Poisson effects model analyzed the association of AKI with hospital length of stay. Results: Thirty-three out of 197 admissions for vaso-occlusive pain crisis (17%) were associated with AKI. Fifty-two percent of the cases presented to the Emergency Room (ER) with AKI. Every one unit decrease in hemoglobin from baseline to admission increased the risk of AKI by 49%. Among patients who received ketorolac for pain, both total days and doses of ketorolac were associated with AKI. Finally, patients with pain and AKI required longer periods of hospitalization than patients without AKI. Conclusion: Acute kidney injury during sickle cell pain crisis is common and may be an important modifiable risk factor for developing chronic kidney disease (CKD). Further studies are needed to determine the impact of nephrotoxic medications on progressive SCD nephropathy.