Purpose: To assess the association between hypometabolic extension of 18F-fluorodeoxyglucose positron emission tomography and diffusion tensor imaging indices, including mean diffusivity (MD) and fractional anisotropy (FA), in hippocampal sclerosis (HS). Methods: Thirty-six unilateral HS were retrospectively selected and stratified into two groups: broad and localized hypometabolic groups (hypometabolism beyond [n = 26] and within the temporal lobe [n = 10]). Forty-one pairs of gray matter (GM) regions of interest (ROIs) were segmented using FreeSurfer software. The GM ROIs were applied to MD maps, and median MD values within each ROI were compared between hemispheres ipsilateral and contralateral to HS using a mixed effect model. Tract-Based Spatial Statistics (TBSS) was used to evaluate FA of white matter (WM) tracts between hemispheres ipsilateral and contralateral to HS. Disease laterality was controlled for. Results: The MD values in the thalamus, caudate, hippocampus, amygdala, superior frontal gyrus, middle and inferior temporal gyrus, temporal pole, and isthmus cingulate gyrus were significantly higher in the HS side than the contralateral side for the broad hypometabolic group. Those in the amygdala and superior temporal sulcus were significantly higher in the HS side than the contralateral side for the localized group. The TBSS analyses showed significantly decreased FA in the WM tracts of the temporal and frontal lobes for the broad hypometabolic group, while no tracts showed significant differences for the localized group. Conclusion: The hypometabolic extension for HS was associated with the abnormalities of MD and FA in GM and WM, respectively, with more widespread microstructural alterations for broad hypometabolic HS.