Background: Although diffusion tensor imaging has been used to monitor Wallerian degeneration, the exact relationship between the evolution of diffusion indices and its underlying pathology, especially in central nervous system, remains largely unknown. Here we aimed to address this question using a cat Wallerian degeneration model of corticospinal tract. Methodology/Principal Findings: Twenty-five domestic mature Felis catus were included in the present study. The evolution of diffusion indices, including mean diffusivity (MD), fractional anisotropy (FA), primary (lambda 1) and transverse eigenvalues (lambda 23) of the degenerated corticospinal tract, were observed at baseline (before modeling) and at 2, 4, 6, 8, 10, 15, 20, 25, 30, 45 and 60 days after modeling in 4 cats. Pathological examinations were performed at eight time points mentioned above. Wallerian degeneration can be detected as early as the 2nd day after modeling by both diffusion tensor imaging and pathology. According to the evolution of diffusion indices, Wallerian degeneration can be classified into 2 stages. During the early stage (within 8 days after modeling), progressive disintegration of axons and myelin sheaths underlies the decreases in FA and lambda 1 and the increase in lambda 23. However, during the late stage (after 8 days), the gradual increases in FA, MD and lambda 1 and the unchanged lambda 23 seem to be a comprehensive reflection of the pathological processes including microglia activation, myelin clearance, and astrocytosis. Conclusions/Significance: Our findings help the understanding of the altered diffusion indices in the context of pathology and suggest that diffusion tensor imaging has the potential to monitor the processes of Wallerian degeneration in the central nervous system in vivo after acute damage.