Post stroke depression (PSD) is a serious complication of stroke. Brain imaging is an important method of studying the mechanism of PSD. However, few studies have focused on the single lesion location. The aim of this study was to investigate the brain mechanism of frontal lobe PSD using combined voxel-based morphometry (VBM) and functional magnetic resonance imaging (fMRI). In total, 30 first-time ischemic frontal lobe stroke patients underwent T1 weighted MRI and resting-state fMRI scans. Clinical assessments included the 24-item Hamilton Rating Scale for Depression, the National Institutes of Health Stroke Scale, and the Mini-Mental State Examination. In our result, decreased gray matter (GM) volume in patients was observed in the prefrontal cortex, limbic system and motor cortex. The anterior cingulate cortex, selected as a seed to perform connectivity analyses, showed a greatly decreased functional connectivity with the prefrontal cortex, cingulate cortex, and motor cortex, but had an increased functional connectivity with the hippocampus gyrus, parahippocampa gyrus, insular, and amygdala. Stroke lesion location reduces excitability of brain areas in the ipsilateral brain. PSD affects mood through the brain network of the prefrontal-limbic circuit. Some brain networks, including motor cortex and the default mode network, show other characteristics of PSD brain network.