Objective To investigate the microstructural abnormalities of white matter in patients with post-stroke depression(PSD) by using the method of voxel-based analysis(VBA). Methods Whole brain diffusion tensor imaging(DTI) was performed in 21 patients with PSD and 22 stroke patients without depression group (PSND), 20 healthy volunteers as control group (NC). Fractional anisotropy(FA) values were compared between PSD group and 2 control groups by VBA. Results The FA values differences with statistical significance of brain regions were found in following (P<0.05): between the PSD group and the NC group, mainly include bilateral frontal lobe and parietal lobe (cortex mainly), the anterior, body and splenium parts of the corpus callosum, the body of cingulate gyrus, corona radiata, basal ganglia(Thalamus, putamen, left internal capsule) and bilateral cerebellar hemisphere(P<0.05), between the PSD group-PSND group, mainly include bilateral medial frontal lobe and parietal lobe cortex (P<0.05), between the PSND group-NC group, mainly include bilateral cingulate gyrus, left anterior and splenium parts of corpus callosum (P<0.05). Conclusion The microstructural abnormalities of white matter were found in patients with early PSD, and mainly expressed as the injury of the nerve loop of the limbic system- cortex-striatum-globus pallidus-dorsal thalamus(LCSPT), which suggested that early PSD may be related to the degree of neural network damage.