Objective To reveal the possible routine of brain network dynamic alterations in patients with mesial temporal lobe epilepsy (mTLE) and to establish a predicted model of seizure recurrence during interictal periods. Methods Seventy-nine unilateral mTLE patients with hippocampal sclerosis and 97 healthy controls from two centers were retrospectively enrolled. Dynamic brain configuration analyses were performed with resting-state functional magnetic resonance imaging (MRI) data to quantify the functional stability over time and the dynamic interactions between brain regions. Relationships between seizure frequency and ipsilateral hippocampal module allegiance were evaluated using a machine learning predictive model. Results Compared to the healthy controls, patients with mTLE displayed an overall higher dynamic network, switching mainly in the epileptogenic regions (false discovery rate [FDR] corrected p-FDR < .05). Moreover, the dynamic network configuration in mTLE was characterized by decreased recruitment (intra-network communication), and increased integration (inter-network communication) among hippocampal systems and large-scale higher-order brain networks (p-FDR < .05). We further found that the dynamic interactions between the hippocampal system and the default-mode network (DMN) or control networks exhibited an opposite distribution pattern (p-FDR < .05). Strikingly, we showed that there was a robust association between predicted seizure frequency based on the ipsilateral hippocampal-DMN dynamics model and actual seizure frequency (p-perm < .001). Significance These findings suggest that the interictal brain of mTLE is characterized by dynamical shifts toward unstable state. Our study provides novel insights into the brain dynamic network alterations and supports the potential use of DMN dynamic parameters as candidate neuroimaging markers in monitoring the seizure frequency clinically during interictal periods.