Sickle cell disease (SCD) predominantly affects individuals of African descent and is characterized by frequent painful vaso-occlusive crises, often requiring opioid management. With the opioid epidemic raising concerns about opioid overdose, this study examines in-hospital outcomes among SCD and non-SCD patients hospitalized for opioid overdose. Using the National Inpatient Sample (NIS) from 2016 to 2021, we analyzed 479,175 opioid overdose hospitalizations, including 1,315 (0.3%) with a concomitant diagnosis of SCD. Propensity score matching was used to balance demographics, comorbidities, and hospital characteristics. SCD patients were younger (45.3% aged 30–49 vs. 33.1%, p < 0.001), predominantly of African descent (92.1% vs. 14.1%, p < 0.001), and more often from lower-income households (58.4% vs. 35.2%, p < 0.001). SCD patients had lower rates of mechanical ventilation (aOR: 0.7, 95% CI: 0.6–0.9) and anoxic brain injury (aOR: 0.5, 95% CI: 0.4–0.8) but experienced longer hospital stays and higher costs. No significant differences in in-hospital mortality were observed (aOR: 0.89, 95% CI: 0.7–1.1, p = 0.34). These findings emphasize the need for a nuanced approach to managing SCD patients during opioid overdose hospitalizations, focusing on mitigating complications, addressing prolonged hospital stays and higher costs, and reducing healthcare disparities through tailored strategies informed by the unique needs of this population.