Cognitive impairment (CI) is reported in 29-57% of patients with neuromyelitis optica spectrum disorder (NMOSD). However, the pathophysiology underlying CI in NMOSD is poorly understood. The present study aims to investigate the predictive values of various conventional and quantitative MRI parameters for cognitive performance in patients with NMOSD. Neurological assessment and conventional, diffusion tensor, and volumetric MRI sequences were collected form 73 patients with NMOSD and 44 healthy controls (HCs). Patients with ≥3 failed tests were considered to have CI. Brain lesion load, gray matter (GM) and white matter (WM) atrophy, deep GM (DGM) atrophy, cortical thickness, and diffuse microstructural WM damage were assessed. Twenty-three (32%) patients with NMOSD had CI. Compared to cognitively preserved (CP) individuals, patients with CI had atrophy in the WM, thalamus, and caudate, decreased fractional anisotropy (FA) and increased mean diffusivity in their WM. A multivariate model indicated that mean FA values in the WM and volume in the nucleus accumbens (NAc) were associated with overall cognition (p = 0.002 and p = 0.008, respectively). Diffuse microstructural damage in the WM and DGM atrophy in the NAc are the strongest predictors of cognitive impairment in patients with NMOSD.