PURPOSE: To prospectively evaluate quantitative diffusion magnetic resonance (MR) imaging for monitoring skeletal muscle injury and repair after femoral artery ligation in mice. MATERIALS AND METHODS: All experimental procedures were approved by the local institutional animal care and use committee. Muscle degeneration and regeneration were induced in 16 mice by using unilateral ligation of the femoral artery. Diffusion-tensor and T2-weighted MR imaging examinations were performed before, immediately after, and 3, 10, and 21 days after ligation. Histologic analysis was also performed at these time points. The dynamic changes in T2 and in five diffusion-tensor imaging indexes were studied by using histogram analysis. Differences between the ligated and nonligated limbs were assessed with paired t tests, and analysis of variance was used to determine temporal evolutions. Parametric maps were clustered to depict regional differences in the responses of the different MR imaging indexes. RESULTS: MR indexes in the ligated limb changed over time (P < .007), and temporal evolutions in the ligated and nonligated limbs differed significantly (P < .001). When ischemia was induced, diffusivity and T2 increased, with a maximum change at 3 days, when most muscle damage was observed at histologic analysis. At 10 days, diffusion values were reduced overall, whereas T2 was still increased. At 21 days, parameter values had largely returned to normal. Changes on the diffusion-tensor and T2 maps had spatial differences, which corresponded to the different phases of tissue regeneration observed at histologic analysis. An additional finding was the transient change in direction of the principal eigenvector during the period of maximal muscle damage. CONCLUSION: After femoral artery ligation, the diffusion-tensor indexes changed dynamically in association with the severity and location of muscle damage.