Multiple sclerosis (MS) is a chronic autoimmune disease characterized by demyelination and neurodegeneration, with emerging evidence suggesting a critical role of brain hypoxia in its progression. While demyelination has been well-studied, the relationship between hypoxia and myelin loss, and how these processes contribute to disease progression, remains poorly understood. This study evaluates the efficacy of quantitative MRI metrics, specifically R2* and quantitative susceptibility mapping, in detecting and differentiating hypoxia and Cuprizone-induced demyelination in the mouse brain. Using a graded hypoxia model (10% vs. 30% oxygen) and Cuprizone treatment, we acquired R2* and QSM data across the mouse brain. An advanced MRI processing pipeline enabled precise detection of regional changes. R2* was highly sensitive to hypoxia, with significant increases observed throughout the brain that correlated with elevated deoxyhemoglobin levels, highlighting R2* as a promising marker for brain oxygenation. Magnetic susceptibility changes were primarily localized to venous structures, underscoring its spatial specificity to paramagnetic compounds. For Cuprizone-induced demyelination, R2* showed a notable decrease in the corpus callosum, suggesting a homogenization effect due to myelin loss, while QSM detected no significant changes, possibly due to a lack of iron accumulation typically seen in demyelinated lesions in human studies. Comparative analyses indicated that R2* responses were more pronounced in hypoxic than demyelinated states, supporting its sensitivity to magnetic inhomogeneities related to deoxyhemoglobin. These findings suggest that R2* and QSM offer complementary insights into hypoxic and demyelinating processes, with potential for enhancing non-invasive imaging in clinical conditions like multiple sclerosis.