Purpose <p>To investigate the concurrent brain structural and functional alterations related to cognition in patients with cerebral small vessel disease (CSVD).</p> Methods <p>Thirty normal controls and 65 CSVD patients, including 33 patients with mild cognitive impairment and 32 patients with no cognitive impairment were included. Structural and resting-state functional MRI measures, including gray matter volume (GMV) and white matter volume (WMV) using voxel-based morphometry (VBM) analysis and amplitude of low-frequency fluctuation (ALFF), were obtained and compared among the three groups. Associations between cognitive scores and ALFF/VBM coupling in the co-altered regions were investigated in CSVD groups.</p> Results <p>Multiple brain regions showed significant differences in GMV and WMV among the three groups (<i>P</i> &lt; 0.01). Abnormal ALFF among the three groups was identified in the left putamen, Rolandic operculum, fusiform gyrus, caudate, parahippocampal gyrus, insula, middle cingulum, bilateral lingual gyrus, and right frontal lobe (<i>P</i> &lt; 0.01). Importantly, a decrease in VBM and increase in ALFF in the left parahippocampal gyrus, caudate and Rolandic operculum, a reduction of the WMV and ALFF in the right superior frontal lobe, and a united rise of GMV and ALFF in the left caudate were detected in CSVD groups. In addition, abnormal ALFF/VBM coupling was significantly related to multiple cognitive assessments.</p> Conclusion <p>The study indicated a reversed pattern of the brain structural deficits and functional activation in the left parahippocampal gyrus, caudate, and Rolandic operculum, suggesting structure–function decoupling in CSVD groups. These might help further understand the pathophysiological mechanism of CSVD.</p>