Microstructural changes after an ischemic stroke (IS) have mainly been described in white matter. Data evaluating microstructural changes in gray matter (GM) remain scarce. The aim of the present study was to evaluate the integrity of GM on longitudinal data using mean diffusivity (MD), and its influence on post-IS cognitive performances. A prospective study was conducted, including supra-tentorial IS patients without pre-stroke disability. A cognitive assessment was performed at baseline and 1 year, including a Montreal Cognitive Assessment, an Isaacs set test, and a Zazzo cancelation task (ZCT): completion time and number of errors. A 3-T brain MRI was performed at the same two time-points, including diffusion tensor imaging for the assessment of GM MD. GM volume was also computed, and changes in GM volume and GM MD were evaluated, followed by the assessment of the relationship between these structural changes and changes in cognitive performances. One hundred and four patients were included (age 68.5 ± 21.5, 38.5% female). While no GM volume loss was observed, GM MD increased between baseline and 1 year. The increase of GM MD in left fronto-temporal regions (dorsolateral prefrontal cortex, superior and medial temporal gyrus, p < 0.05, Threshold-Free Cluster Enhancement, 5000 permutations) was associated with an increase time to complete ZCT, regardless of demographic confounders, IS volume and location, GM, and white matter hyperintensity volume. GM integrity deterioration was thus associated with processing speed slowdown, and appears to be a biomarker of cognitive frailty. This broadens the knowledge of post-IS cognitive impairment mechanisms. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.< Leer menos