Introduction: Diaphragm function may be impaired in children with sickle cell disease (SCD). We hypothesized that diaphragm function is related to performance and ventilation on the 6-min walk test (6MWT).Methods: Respiratory muscle testing, diaphragm ultrasonography, and the 6MWT with portable gas analysis were performed on children with SCD and age-and sex-matched controls.Results: Fourteen children with SCD were enrolled. Comparisons were made between nine children with SCD (9.89 ± 2.93 years) and nine controls (10.33 ± 2.35 years). Diaphragm thickness at total lung capacity, thickening fraction, and excursion time during quiet breaths and deep breaths (DB), all normalized by forced vital capacity, were greater in children with SCD (p< 0.05 for all). 6MWT distance was shorter in children with SCD (450.87 ± 74.2 m vs. 579.22 ± 72.46 m, p = 0.01). Tidal volume (V T ), minute ventilation (V E ̇), and oxygen consumption (V O2 ̇) were also lower (p< 0.05 for all). DB excursion correlated positively with 6MWT distance (r = 0.648, p = 0.023) and negatively with rate of perceived exertion (RPE) (r = −0.759, p = 0.003). RPE correlated negatively with distance (r = −0.680, p = 0.015). DB excursion time correlated positively with distance (r = 0.611, p = 0.035), V T (r = 0.770, p = 0.009), V E ̇(r = 0.736, p = 0.015), and V O2 ̇(r = 0.751, p = 0.012).Conclusions: Increased diaphragm excursion may be a strategy used to relieve air hunger while longer excursion time may reflect compensations to increase lung recruitment. Further studies are needed to better understand how these mechanisms affect exercise tolerance in children with SCD.