Purpose Sickle cell disease (SCD) is a significant burden for patients and healthcare systems due to multiple factors, including high readmission rates. This study aimed to determine the general characteristics, etiology of admissions, annual admission rate, length of stay, and readmission rate of patients with SCD. Patients and Methods This retrospective observational study included all adult patients with SCD admitted to the General Internal Medicine (GIM) unit between 2016 and 2021. Results There were 160 patients (mean age, 31.08 ± 9.06 years; 51.25% female) with SCD included in this study. Most originated from southern Saudi Arabia (45.62%). The average annual number of emergency department (ED) visits was 4, and approximately 19% of patients had ≥3 annual admissions. The mean length of stay was 6 days. The readmission rates at 7, 30, 60, and 90 days were 8%, 24.5%, 13.6%, and 10.8%, respectively. Conclusion SCD generates a significant economic burden on the Saudi society and the effects on the healthcare system and patients’ quality of life are evident in the high ED visits, readmission rates and prolonged hospitalization. Thereupon we advocate the implementation of sickle cell disease-specialized multidisciplinary clinics.