Importance Guidelines for the timely emergency department (ED) administration of opioids for acute sickle cell disease (SCD) pain lack clear evidence showing associations with reduced hospitalizations. Objective To evaluate the associations between the timely administration of multiple opioid doses during uncomplicated SCD pain episodes in children and hospitalization. Design, Setting, and Participants This multisite cross-sectional study used data from the Pediatric Emergency Care Applied Research Network Registry. Included were 12 pediatric EDs from children’s hospitals with comprehensive SCD centers across the US. ED visits by children younger than 19 years with uncomplicated SCD pain at any of the 12 sites between January 1, 2019, and December 31, 2021, were included. Primary diagnosis codes were used to identify visits for SCD pain; visits with any other SCD complication were excluded. Initial data analysis was conducted from April 2024 to April 2025, including revisions. After-revision analyses were done between May and June of 2025. Exposures The 2 exposures of interest were as follows: (1) time from ED arrival to first opioid administration (dichotomized as ≤60 minutes of arrival vs &gt;60 minutes from arrival) and (2) time interval between the first and the second opioid administration (dichotomized in separate analyses as ≤30 minutes vs &gt;30 minutes, ≤45 minutes vs &gt;45 minutes, and ≤60 minutes vs &gt;60 minutes). Main Outcomes and Measures The primary outcome was hospitalization at the end of an ED visit. Results A total of 2538 patients (mean [SD] age, 12.0 [5.0] years; 1293 male [50.9%]) were included in this study. Of 9233 ED visits, 5023 (54.4%) resulted in hospitalization. First-dose timeliness of opioid administration evaluated alone was associated with decreased hospitalizations (odds ratio [OR], 0.84; 95% CI, 0.75-0.95). Evaluating combined first- and second-dose timeliness of opioid administration for the 7853 visits (85.1%) with 2 or more opioid doses, first-opioid timeliness was associated with reduced odds of hospitalization, even when the second dose was outside 30 minutes (OR, 0.85; 95% CI, 0.74-0.98) or 45 minutes (OR, 0.84; 95% CI, 0.72-0.97). First-dose timeliness combined with a second dose within 30-minute (OR, 0.62; 95% CI, 0.52-0.75), 45-minute (OR, 0.70; 95% CI, 0.59-0.83), and 60-minute (OR, 0.78; 95% CI, 0.67-0.92) intervals achieved the lowest odds of hospitalization. Conclusions and Relevance This cross-sectional study found that timely receipt of opioids was associated with a reduction in hospitalizations for SCD pain. The largest decrease in hospitalization was achieved with the first dose within 60 minutes and the second dose within 30 minutes; however, longer second-dose durations were associated with reduced hospitalizations.