Purpose: The purpose of this study was to examine for differences in mean oxygenation levels of healthy pediatric patients and pediatric patients with sickle cell disease (SCD) receiving nitrous oxide (N₂O) for dental procedures and to determine if N₂O decreases oxygen saturation levels for SCD patients. Methods: Patients aged 2 to 17 years with SCD and healthy age-matched patients were recruited at their preventive or restorative dental visits between 2019 and 2023. Up to 50% N₂O was administered during routine restorative treatment. Oxygen saturation was measured via a pulse oximeter before starting nitrous, at 10-minute intervals throughout treatment, and after nitrous oxide termination. Descriptive and bivariate analyses were conducted using statistical software with statistical significance set at P<0.05. Results: There was a significant difference in average oxygen saturation at baseline between cases and controls; however, there was no significant difference at 10, 20, or 30 minutes. There was no significant difference in oxygen saturation between cases and controls after terminating N₂O. Conclusions: Use of up to 50% nitrous oxide for dental treatment was found to be safe in this cohort of sickle cell disease patients. The oxygen saturation of healthy patients and patients with SCD increases with the use of N₂O. In addition, N₂O use in patients with SCD may alleviate anxiety and increase the pain threshold, decreasing the risk for vaso-occlusive crisis.