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Sickle cell disease (SCD) is a major chronic hematologic disorder in Saudi Arabia associated with recurrent vaso-occlusive crises (VOCs), acute pain episodes, and heavy reliance on emergency department (ED) visits. Despite improvements in survival, longitudinal data on ED utilization patterns and their determinants remain limited in the region. Therefore, the aim of this study is to assess temporal trends and predictors of ED utilization among patients with SCD across multiple tertiary centers in Saudi Arabia between 2016 and 2021. This multicenter retrospective cohort study analyzed data from the National Guard Health Affairs (NGHA) electronic health record (EHR) system across five hospitals (Riyadh, Jeddah, Madinah, Dammam, and Al-Ahsa). The study included all patients with a confirmed SCD diagnosis (ICD-10 code D57) and at least one ED visit during the study period. After applying the eligibility criteria, 691 patients were included. Demographics, comorbidities, hospital region, and prescribed ED medications, including opioids, non-steroidal anti-inflammatory drugs (NSAIDs), neuropathic agents, and benzodiazepines. The primary outcome was annual ED visits per patient. Multivariable negative binomial regression estimated incidence rate ratios (IRRs) with 95% confidence intervals (CIs), adjusted for demographics, comorbidities, and clustering by hospital site. The cohort [mean (SD) age, 26.5 (13.6) years; 350 (50.7%) men] showed a sharp rise in ED visits from 9.2 visits in 2016 to 38.8 in 2021 (relative increase, + 76.3%; < 0.001). Hospital admissions also rose from 6.3 to 13.6 ( < 0.001). In 2021, the mean ED visit rate [38.83 (2) ± 10.59] exceeded the threshold for high ED utilization > 33. Male gender (IRR, 1.52; 95% CI, 1.28-1.81; < 0.001), older age (per 10 years: IRR, 1.27; 95% CI, 1.08-1.50; = 0.006), and asthma (IRR, 1.29; 95% CI, 1.04-1.60; = 0.02) predicted higher ED utilization. Opioids were prescribed in 96.5% of visits, mostly for single-day use (93.5%). ED utilization among patients with SCD from the NGHA hospitals in Saudi Arabia rose substantially between 2016 and 2021, reflecting both clinical severity and system-level care gaps. Our findings highlight the need for standardized pain protocols, comprehensive outpatient services, and Vision 2030-aligned transformations to reduce preventable ED dependence.