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Abstract Background CD44, a hyaluronan receptor expressed by glial and progenitor cells, has been implicated in neuroinflammation and impaired remyelination. We investigated changes in CD44 expression and cell morphology in the corpus callosum (CC) during toxin-induced demyelination and subsequent spontaneous remyelination. Materials and Methods Thirty adult male C57BL/6 mice were assigned to three groups (n = 10/ group): control, demyelination (0.2% cuprizone for 5 weeks), and remyelination (5 weeks of cuprizone followed by 5 weeks of recovery). CD44 immunohistochemistry was performed on coronal CC sections. Quantification was carried out in the medial CC (three sections per animal, five non-overlapping fields per section; total n = 150 visual fields per group). Morphological features of CD44+ cells were assessed qualitatively. Group differences were analyzed using the Kruskal–Wallis test with Dunn’s post-hoc comparisons. Results In the controls, CD44 immunoreactivity was sparse and primarily localized to the perinuclear region. Demyelination resulted in a marked increase in CD44 labeling, with CD44+ cells being substantially more numerous and exhibiting multiple cytoplasmic processes consistent with an activated astrocytic phenotype. During remyelination, CD44 labeling persisted but with fewer and shorter processes, indicating partial reversion toward a less activated morphology. Mean CD44+ cells per field were 19 (control), 57 (demyelination), and 32 (remyelination), corresponding to densities of 183, 528, and 426 cells/mm², respectively (control < remyelination < demyelination). Differences among groups were significant (Kruskal– Wallis, p < 0.001), and all pairwise comparisons were significant (Dunn’s test, p < 0.001). Conclusions Cuprizone-induced demyelination triggers robust upregulation of CD44 and an activated astrocyte–like morphology in the CC, which partially normalizes during remyelination. These results highlight the dynamic regulation of CD44 during white matter injury and recovery and support further investigation into its mechanistic role in remyelination.