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Purpose: The association between obstructive sleep apnea (OSA) and cognitive impairment is well-recognized, but little is known about neural derangements that underlie this phenomenon. The purpose of this study was to evaluate the utility of diffusion kurtosis imaging (DKI) using a whole-brain atlas to comprehensively assess microstructural tissue changes in the brain of patients with OSA. Methods: This prospective study was conducted in 20 patients with moderate-to-severe OSA and 20 age- and gender-matched controls. MRI data acquisition was performed with 3 Tesla and data was analyzed using a whole-brain atlas. DKI data were processed and transformed into a brain template space to obtain various kurtosis parameters including axial kurtosis (AK), radial kurtosis (RK), mean kurtosis (MK), and kurtosis fractional anisotropy (KFA) using a 189-region brain atlas in the same template space. These kurtosis measurements were further analyzed using a student t-test in order to determine kurtosis measurements that present significant differences between the OSA patient set and the control set. Results: Significant differences (P < 0.05) were found in AK (54 regions), RK (10 regions), MK (6 regions) and KFA (41 regions) values in patients with OSA as compared to controls. DKI indices, using an atlas-based whole-brain analysis approach used in our study, showed widespread involvement of the anatomical regions in patients with OSA. Conclusion: The kurtosis parameters are more sensitive in demonstrating abnormalities in brain tissue structural organization at the microstructural level before any detectable changes appear in conventional MRI or other imaging modalities.