Background: The integrity of the autonomic nervous system (ANS) is essential for keeping physiological processes stable, even under stress. Since there is growing interest in heart rate variability (HRV) analysis for the noninvasive assessment of the ANS in sickle cell anemia (SCA) patients, we studied the behavior of the ANS in the presence of a stressor that simulates daily-life multitasking, the Glittre ADL test (GA-T). Objectives: To evaluate the involvement of the ANS using HRV in adults with SCA during the GA-T and to quantify the strength of the correlation of HRV with lung and muscle functions. Methods: In this cross-sectional study, 16 adults with SCA and 12 healthy controls without sickle cell disease underwent HRV assessment during the GA-T, pulmonary function tests (spirometry, diffusing capacity for carbon monoxide (DLCO), and respiratory muscle testing). Peripheral muscle function [handgrip strength (HGS) and quadriceps strength (QS)] were also measured. Results: Compared to the healthy controls, adults with SCA showed lower HRV, with worse parasympathetic modulation due to reductions in the following indices: the root-mean-square difference of successive normal iRRs (iRR) (RMSSD); the percentage of pairs of consecutive iRRs whose difference is > 50 m (pNN50); the high-frequency component of heart rate variability (HF); and the standard deviation of instantaneous beat-to-beat variability (SD1) (P < 0.001 for all). Compared to healthy controls, individuals with SCA showed greater sympathovagal imbalance (higher ratio between low-frequency and HF components) and lower complexity of the ANS (lower approximate entropy). The GA-T time was correlated with parasympathetic activity indices: RMSSD (rs = -0.650, P < 0.01); pNN50 (rs = -0.932, P < 0.0001), HF (rs = -0.579, P < 0.01), and SD1 (rs = -0.814, P < 0.0001). Correlations between parasympathetic activity indices and DLCO, HGS, and QS measures were also significant. Conclusions: Adults with SCA have low HRV, with low parasympathetic activity, sympathovagal imbalance, and abnormal ANS complexity. In addition, lower HRV is associated with longer GA-T time, greater impairment of pulmonary diffusion, and greater muscle strength dysfunction.