Background The mechanisms of vagal nerve stimulation (VNS) for the treatment of drug-resistant epilepsy (DRE) remain unclear. This study aimed to measure spontaneous brain activity changes caused by VNS in DRE patients using resting-state functional MRI (rs-fMRI). Methods The rs-fMRI scans were performed in 16 DRE patients who underwent VNS surgery. Amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) was generated and examined using paired sample t-test to compare activity changes at different current intensity stage. The preoperative and postoperative ALFF/ReHo were also compared in eight responders (>= 50% reduction of seizure frequency three months after surgery) and eight nonresponders using paired sample t-test. Results The significant ALFF and ReHo changes were shown in various cortical/subcortical structures in patients under different current intensity. After three months of stimulation, responders exhibited increased ALFF in the right middle cingulate gyrus, left parahippocampal gyrus, and left cerebellum, and increased ReHo in the right postcentral gyrus, left precuneus, left postcentral gyrus, right superior parietal gyrus, right precentral gyrus, and right superior frontal gyrus. Nonresponders exhibited decreased ALFF in the left temporal lobe and right cerebellum, increased ALFF in bilateral brainstem, decreased ReHo in bilateral lingual gyri, and increased ReHo in the right middle frontal gyrus and right anterior cingulate gyrus. Conclusions The spontaneous neural activity changes in DRE patients caused by VNS were in an ongoing process. Increased ALFF/ReHo in frontal cortex, cingulate gyri, precentral/postcentral gyri, parahippocampal gyri, precuneus, parietal cortex, and cerebellum may implicate in VNS-induced improvement in seizure frequency.